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Ganoderma lucidum, a medicinal mushroom with a long history in traditional Chinese medicine, is widely used for chronic diseases. Ganospirones A-G (1-7), seven pairs of undescribed spiro-meroterpenoids, were isolated from the fruiting bodies of G. lucidum. Their structures including absolute configurations were characterized by using NMR spectroscopic data, ECD computational and X-ray diffraction methods. The anti-inflammatory and anti-renal fibrosis activities of the meroterpenoids 1-7 were tested, and the results revealed that (-)-2 and (+)-2 could inhibit iNOS expression in lipopolysaccharide-induced RAW264.7 cells at 20 μM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Fungal infections pose a great threat to public health and there are only four main types of antifungal drugs, which are often limited with toxicity, drug-drug interactions and antibiotic resistance. Streptomyces is an important source of antibiotics, represented by the clinical drug amphotericin B. Here we report the discovery of alligamycin A (1) as an antifungal compound from the rapamycin-producer Streptomyces iranensis through genome-mining, genetics and natural product chemistry approaches. Alligamycin A harbors a unique chemical scaffold with 13 chiral centers, featuring a β-lactone moiety, a [6,6]-spiroketal ring, and an unreported 7-oxo-octylmalonyl-CoA extender unit incorporated by a potential crotonyl-CoA carboxylase/reductase. It is biosynthesized by a type I polyketide synthase which is confirmed through CRISPR-based gene editing. Alligamycin A displayed potent antifungal effects against numerous clinically relevant filamentous fungi, including resistant Aspergillus and Talaromyces species. β-Lactone ring is essential for the antifungal activity since alligamycin B (2) with disruption in the ring abolished the antifungal effect. Proteomics analysis revealed alligamycin A potentially disrupts the integrity of fungal cell walls and induces the expression of stress-response proteins in Aspergillus niger. Discovery of the potent antifungal candidate alligamycin A expands the limited antifungal chemical space., (© 2024. The Author(s).)

Breviane spiroditerpenoids are a small group of structurally interesting and complex meroterpenoids. This work focused on an endophytic fungus Penicillium bialowiezense ZBWPQ-27 that was isolated from a medicinal plant Euphorbia neriifolia , leading to the isolation of 15 breviane spiroditerpenoids with four types of polycyclic systems ( 1 - 6 and 9 - 17 ), and two new carotane sesquiterpenoids ( 7 and 8 ). The structures including absolute configurations of the new compounds 1 - 8 were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. In addition, the misassigned NMR data of several resonances of the 5-methyl-TAL motif (E ring) in those of known brevianes ( 9 - 15 ) were corrected by spectroscopic data analysis. Biological tests revealed that brevianes with the type A ring system (6/6/6/5/6) showed moderate to significant immunosuppressive activities, and compound 11 displayed the most potent inhibitory activities against concanavalin A (ConA)-induced T cell proliferation (IC 50 4.1 ± 0.2 μM) and lipopolysaccharide (LPS)-induced B cell proliferation (IC 50 4.6 ± 0.2 μM), with good SI values of 28 ± 2 and 25 ± 4, respectively.

Spirotetramat is a frequently used insecticide in integrated pest management (IPM) strategies against rosy apple aphid (Dysaphis plantaginea) and woolly apple aphid (Eriosoma lanigerum) in apple cultivation. It is known that paraffin oil adjuvants increase the effect of spirotetramat against aphids. In contrast, there is a knowledge gap regarding the effects of co-applied paraffin (mineral or petroleum) oil on the degradation of spirotetramat and its metabolites (B-enol, B-keto, B-mono, and B-glu), which has not been previously investigated. Spirotetramat combined with formulated paraffin oil was tested against two aphid species and the residues of spirotetramat and its metabolites on leaves and apples were quantified using Liquid Chromatography coupled with tandem Mass Spectrometry (LC-MS/MS). The results showed that spirotetramat is highly effective against D. plantaginea, decreasing infestation by almost 100%. Furthermore, spirotetramat was shown to be effective against E. lanigerum, the reduction in infestation ranged between 67.9 and 97.7% during the last validation date. The addition of paraffin oil increased the effect of spirotetramat and affected its degradation, indicating that its efficacy could be connected to its metabolites. B-mono and B-glu were the most persistent metabolites in apple fruit overall when paraffin oil was applied., (© 2024. The Author(s).)

An approach to the synthesis of phosphoryl substituted spiro-1,3-dioxolane oxindoles was developed from the base-catalyzed reaction of various isatins with (3-hydroxyprop-1-yn-1-yl)phosphonates. It was found that various aryl-substituted and N-functionalized isatins with the formation of appropriate products with high yields and stereoselectivity when using t -BuOLi are able to react. Cytotoxic activity evaluation suggests that the most significant results in relation to the HuTu 80 cell line were shown by N-benzylated spirodioxolanes. 5-Cloro- N -unsubstituted spirooxindoles exhibit antiaggregational activity exceeding the values of acetylsalicylic acid.

Cephalostatins and ritterazines represent fascinating classes of dimeric marine derived steroidal alkaloids with unique chemical structures and promising biological activities. Originally isolated from marine tube worms and the tunicate Ritterella tokioka collected off the coast of Japan, cephalostatins and ritterazines display potent anticancer effects by inducing apoptosis, disrupting cell cycle progression, and targeting multiple molecular pathways. This review covers the chemistry and bioactivities of 45 cephalostatins and ritterazines from 1988 to 2024, highlighting their complex structures and medicinal contributions. With insights into their structure activity relationships (SAR). Key structural elements, such as the pyrazine ring and 5/6 spiroketal moieties, are found crucial for their biological effects, suggesting interactions with lipid membranes or hydrophobic protein domains. Additionally, the formation of oxocarbenium ions from spiroketal cleavage may enhance their potency by covalently modifying DNA. The pharmacokinetics, ADMET and Drug likeness properties of these steroidal alkaloids are thoroughly addressed. Drug likeness analysis shows that these compounds fit well with the Rule of 4 (Ro4) for Protein-Protein Interaction Drugs (PPIDs), underscoring their potential in this area. Ten compounds (20, 27, 33, 34, 39, 40, 41, 42, 43, and 45) have demonstrated favourable pharmacokinetic and ADMET profiles, making them promising candidates for further research. Future efforts should focus on alternative administration routes, structural modifications, and innovative delivery systems, such as prodrugs and nanoparticles, to improve bioavailability and therapeutic effects. Advances in synthetic chemistry, mechanistic insights, and interdisciplinary collaborations will be essential for translating cephalostatins and ritterazines into effective anticancer therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

An unprecedented spiro-C-glycoside adduct, heteryunine A (1), along with two uncommon alkaloids featuring a 2,3-diketopiperazine skeleton, heterpyrazines A (2) and B (3), were discovered in the roots of Heterosmilax yunnanensis. The detailed spectroscopic analysis helped to clarify the planar structures of these compounds. Compound 1, containing 7 chiral centers, features a catechin fused with a spiroketal and connects with a tryptophan derivative by a CC bond. Its complex absolute configuration was elucidated by rotating frame overhauser enhancement spectroscopy (ROESY), specific rotation, and the 13 C nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculation. The possible biosynthetic routes for 1 were deduced. Compounds 1 and 2 showed significant antifibrotic effects and further research revealed that they inhibited the activation, migration and proliferation of hepatic stellate cells (HSCs) through suppressing the activity of Ras homolog family member A (RhoA)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Plants have numerous defensive secondary metabolites to withstand insect attacks. Scoparone, which is extracted from the medicinal plant Artemisia capillaris, has potent acaricidal effects on Tetranychus cinnabarinus. Spirodiclofen, derived from a tetronic acid derivative, is a potent commercial acaricide that is extensively used globally. However, whether scoparone has synergistic effects when used in conjunction with spirodiclofen and the underlying synergistic mechanism remains unclear., Results: Scoparone exhibited a potent synergistic effect when it was combined with spirodiclofen at a 1:9 ratio. Subsequently, cytochrome P450 monooxygenase (P450) activity, RNA-Seq and qPCR assays indicated that the enzyme activity of P450 and the expression of one P450 gene from T. cinnabarinus, TcCYP388A1, were significantly inhibited by scoparone and spirodiclofen + scoparone; conversely, P450 was activated in spirodiclofen-exposed mites. Importantly, RNAi-mediated silencing of the TcCYP388A1 gene markedly increased the susceptibility of spider mites to spirodiclofen, scoparone and spirodiclofen + scoparone, and in vitro, the recombinant TcCYP388A1 protein could metabolize spirodiclofen. Molecular docking and functional analyses further indicated that R117, which is highly conserved in Arachnoidea species, may be a vital specific binding site for scoparone in the mite TcCYP388A1 protein. This binding site was subsequently confirmed using mutagenesis data, which revealed that this binding site was the sole site selected by scoparone in spider mites over mammalian or fly CYP388A1., Conclusions: These results indicate that the synergistic effects of scoparone and spirodiclofen on mites occurs through the inhibition of P450 activity, thus reducing spirodiclofen metabolism. The synergistic effect of this potent natural product on the detoxification enzyme-targeted activity of commercial acaricides may offer a sustainable strategy for pest mite resistance management. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Maintenance therapy with buprenorphine and methadone is the gold standard pharmacological treatment for opioid use disorder (OUD). Despite these compounds demonstrating substantial efficacy, a significant number of patients do not show optimal therapeutic responses. The abuse liability of these medications is also a concern. Here we used rats to explore the therapeutic potential of the new long-acting pan-opioid agonist Cebranopadol in OUD. We tested the effect of cebranopadol on heroin self-administration and yohimbine-induced reinstatement of heroin seeking. In addition, we evaluated the abuse liability potential of cebranopadol in comparison to that of heroin under fixed ratio 1 (FR1) and progressive ratio (PR) operant self-administration contingencies. Oral administration of cebranopadol (0, 25, 50 μg/kg) significantly attenuated drug self-administration independent of heroin dose (1, 7, 20, 60μg/inf). Cebranopadol also reduced the break point for heroin (20 μg/inf). Finally, pretreatment with cebranopadol significantly attenuated yohimbine-induced reinstatement of drug seeking. In abuse liability experiments under FR1 contingency, rats maintained responding for heroin (1, 7, 20, 60μg/inf) to a larger extent than cebranopadol (0.03, 0.1, 0.3, 1.0, 6.0μg/inf). Under PR contingency, heroin maintained responding at high levels at all except the lowest dose, while the break point (BP) for cebranopadol did not differ from that of saline. Together, these data indicate that cebranopadol is highly efficacious in attenuating opioid self-administration and stress-induced reinstatement, while having limited abuse liability properties. Overall, the data suggest clinical potential of this compound for OUD treatment., Competing Interests: Declaration of competing interest The authors declare that, at the time the study was conducted, they had no competing or conflicting interest. RC is now consultant for Tris-Therapeutic. A preprint of this manuscript has been published in Biorvix ID#: BIORXIV/2023/550008., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The two-spotted spider mite, Tetranychus urticae Koch (TSSM), is an important cosmopolitan pest of agricultural crops that is often managed in greenhouses by augmentation of predatory mites in combination with acaricides. Here we examined the transgenerational effects of low lethal concentrations of a widely-used acaricide, Oberon Speed® (a combination of spiromesifen and abamectin), on the life history traits and population growth of T. urticae and two of its predators, Phytoseiulus persimilis Athias-Henriot and Amblyseius swirskii Athias-Henriot (Acari: Phytoseiidae). The concentrations employed corresponded to the LC 10 , LC 20 and LC 30 values estimated for TSSM protonymphs 48 h post-exposure in a topical bioassay, which yielded an LC 50 value of 207.2 ppm. Parental exposure of TSSM to all three low concentrations increased the total developmental time of progeny; both the LC 20 and LC 30 treatments reduced adult longevity and number of oviposition days, but only the LC 30 treatment increased the preoviposition period. Similarly, both the LC 20 and LC 30 treatments significantly reduced life table parameters (r, R 0 , λ, and GRR), and increased generation time (T) and population doubling time (DT). Although maternal exposure to the acaricide had various impacts on progeny life history, A. swirskii was less affected than P. persimilis, suggesting the former species would be more compatible for integration with Oberon Speed® for control of T. urticae in greenhouse vegetable production., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural basis for itch remains unclear. Here, we used two-photon Ca 2+ imaging of the dorsal horn to visualize neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal interneurons recruited by diverse itch-causing stimuli that represents a subset of neurons that express the gastrin-releasing peptide receptor (GRPR). Moreover, we find that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nuclei. We then show that the kappa opioid receptor agonist nalfurafine relieves itch by selectively inhibiting GRPR spinoparabrachial neurons. These experiments provide a population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.

We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Green lacewing, Chrysoperla carnea (Stephens) is a generalist predator used as a biological control agent in agro ecosystems. In order to use chemical and biological control in an integrated way, it is advantageous to know about natural enemy resistance response to a selected chemical. To determine C. carnea spirotetramat resistance potential, a population collected from the field was selected in the laboratory. Then we determined how spirotetramat resistance was inherited and how much it impacts the fitness of C. carnea. After eighteen selections with spirotetramat, the selected population (Spiro-Sel) of C. carnea had a 47-fold of resistance when compared to an UNSEL population. Inheritance results showed that spirotetramat resistance was inherited as an autosomal, incompletely dominant and polygenic trait. The values of effective dominance decreased from 0.87 (incomplete dominant) to 0.00 (complete recessive) as the concentration of spirotetramat increased from 625 mg/L to 10000 mg/L. The Spiro-Sel strain had no cross resistance to chlorfenapyr (1.10-fold), deltamethrin (1.26-fold) and chlorpyrifos (1.27-fold). After 7 generations without selection pressure resistance to all experimental insecticides in the Spiro-Sel strain was stable. Fitness data of the Spiro-Sel, Cross A, Cross B, UNSEL and susceptible strains of C. carnea showed that spirotetramat resistance increased the fitness of the selected green lacewing population. Life history parameters like fecundity, net reproductive rate, and relative fitness of the Spiro-Sel strain significantly increased when compared to the susceptible or unselected strains of C. carnea. These findings show that C. carnea is a perfect candidate for integrated pest management (IPM) programmes that combine biological control methods with selective pesticide applications to manage a variety of insect pests. Additionally, it would reduce the possibility of pests developing pesticide resistance despite repeated applications. It would be an excellent choice for widespread releases and be effective in most spray programs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hassan, Shad. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The invasive golden apple snail Pomacea canaliculata is one of the devastating threats to aquatic ecosystems and wetland agriculture worldwide. Macrolides from microbes display various advantages over other compounds in controlling snails. However, emergence of antibiotic-resistant phenotypes against certain macrolides in the field appeals for exploring more effectively molluscicidal macrolides. Here, two borrelidins, borrelidin BN1 and BN2, from the extract of a Streptomyces strain fermentation were evaluated for molluscicidal potential against P. canaliculata using both immersion and contact bioassay methods. Borrelidin BN1 (borrelidin A) presented a significant molluscicidal activity comparable to the chemical pesticide metaldehyde, and had a much lower median lethal concentration value (LC 50 , 522.984 μg·ml -1 ) than avermectin B1 at 72 h of contact-killing treatment. Snail growth was inhibited by borrelidin BN1 more than by metaldehyde at sublethal concentrations, consistent with responses of key biochemical parameters. Exposure to borrelidin BN1 decreased the activity of acetylcholinesterase (AChE), glutathione S-transferase (GST), aspartate aminotransferase (AST), alanine aminotransferase (ALT) as well as the levels of energy reserves and sex steroids in snail tissues, while increased the activity of superoxide dismutase (SOD), catalase (CAT), lactate dehydrogenase (LDH) and the level of lipid peroxidation (LPO). Further application assay confirmed that borrelidin BN1 protected crop plant Zizania latifolia from P. canaliculata damage via suppressing snail population density. These findings suggest great potential of borrelidin BN1 as a molluscicide. Additionally, its higher activity than the stereoisomeric borrelidin BN2 (borrelidin F) implied better molluscicidal borrelidins could be acquired through structural optimization., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A novel spiro [pyrrolidine-3',3'-quinoline]-2,2'-dione scaffold was constructed using fragments of quinoline and pyrrolidine. Subsequently, two series of derivatives were designed based on this scaffold. The enzyme inhibition experiments revealed that all designed compounds had moderate to good inhibitory activity against chitin synthase (CHS). The inhibitory effects of compounds 5i, 5j, 8i and 8n were approximately equal to that of control drug polyoxin B (PB, IP = 86.4 ± 2.9 %, IC 50  = 0.082 ± 0.013 mM) which is a well-established CHS inhibitor. The results from enzyme kinetic parameters assays proved that these compounds act as non-competitive inhibitors of CHS. The sorbitol protection experiments demonstrated the tested compounds disrupted the synthesis of cell wall, which further verified that the target of these compounds is CHS. The experiments of antimicrobial showed that compounds 5b, 5f, 5i, 5j, 8f, 8i, 8m, 8n and 8o had strong antifungal activity against the four tested pathogenic fungi strains frequently emerging in clinical setting, with MIC values ranging from 4 to 32 μg/mL, which were either superior to or comparable with those of PB or fluconazole. Furthermore, these compounds displayed synergistic or additive effects when combined with fluconazole and these active compounds also showed promising activity against fluconazole-resistant and micafungin-resistant fungi variants. The result of antimicrobial experiments indicated that these compounds had minimal activity to tested bacterial strains. This suggests that they had selective antifungal activity. The results of ADME prediction, in conjunction with the cytotoxicity assay results, indicated that these compounds had favorable pharmacokinetic profiles and low toxicity. In addition, molecular docking studies illustrated that the compound had a strong affinity with the CHS, which was consistent with the results of enzymatic assays. These findings indicated that the designed compounds are non-competitive inhibitors of CHS with good selectivity and broad-spectrum antifungal activity, and possess significant antifungal activity against drug-resistant fungi, suggesting their potential as lead compounds for the development of novel drugs against drug-resistant fungi., Competing Interests: Declaration of competing interest I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. I declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Twelve spiro thiazolidinone compounds (A-L) were synthesized via either conventional thermal or ultrasonication techniques using Fe 2 O 3 nanoparticles. The modification of the traditional procedure by using Fe 2 O 3 nanoparticles led to enhancement of the yield of the desired candidates to 78-93% in approximately half reaction time compared with 58-79% without catalyst. The products were fully characterized using different analytical and spectroscopic techniques. The structure of the two derivatives 4-phenyl-1-thia-4-azaspirodecan-3-one (A) and 4-(p-tolyl)-1-thia-4-azaspirodecan-3-one (B) were also determined using single crystal X-ray diffraction and Hirshfeld surface analysis. The two compounds (A and B) were crystallized in the orthorhombic system with Pbca and P2 1 2 1 2 1 space groups, respectively. In addition, the crystal packing of compounds revealed the formation of supramolecular array with a net of intermolecular hydrogen bonding interactions. The energy optimized geometries of some selected derivatives were performed by density functional theory (DFT/B3LYP). The reactivity descriptors were also calculated and correlated with their biological properties. All the reported compounds were screened for antimicrobial inhibitions. The two derivatives, F and J, exhibited the highest levels of bacterial inhibition with an inhibition zone of 10-17 mm. Also, the two derivatives, F and J, displayed the most potent fungal inhibition with an inhibition zone of 15-23 mm. Molecular docking investigations of some selected derivatives were performed using a B-DNA (PDB: 1BNA) as a macromolecular target. Structure and activity relationship of the reported compounds were correlated with the data of antimicrobial activities and the computed reactivity parameters., (© 2024. The Author(s).)

Neurons co-expressing kisspeptin, neurokinin B, and dynorphin A (KNDy neurons), located in the arcuate nucleus (ARC) of the hypothalamus, are indicated to be the gonadotropin-releasing hormone (GnRH) pulse generator. Dynorphin A is reported to suppress GnRH pulse generator activity. Nalfurafine is a selective agonist of the κ-opioid receptor (KOR), a receptor for dynorphin A, clinically used as an anti-pruritic drug. This study aimed to evaluate the effects of nalfurafine on GnRH pulse generator activity and luteinizing hormone (LH) pulses using female goats. Nalfurafine (0, 2, 4, 8, or 16 μg/head) was intravenously injected into ovariectomized Shiba goats. The multiple unit activity (MUA) in the ARC area was recorded, and plasma LH concentrations were measured 2 and 48 h before and after injection, respectively. The MUA volley interval during 0-2 h after injection was significantly increased in the nalfurafine 8 and 16 μg groups compared with the vehicle group. In 0-2 h after injection, the number of LH pulses was significantly decreased in the nalfurafine 8 and 16 μg groups, and the mean and baseline LH were significantly decreased in all nalfurafine-treated groups (2, 4, 8, and 16 μg) compared with the vehicle group. These results suggest that nalfurafine inhibits the activity of the GnRH pulse generator in the ARC, thus suppressing pulsatile LH secretion. Therefore, nalfurafine could be used as a reproductive inhibitor in mammals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was partly supported by funds donated by Toray Industries, Inc., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Overexpression of carboxyl/cholinesterase (CCE) genes has been reported to be associated with many cases of pesticide resistance in arthropods. However, it has been rarely documented that CCE genes participate in spirodiclofen resistance in Panonychus citri . In previous research, we found that spirodiclofen resistance is related to increased P450 and CCE enzyme activities in P. citri . In this study, we identified two CCE genes, PcCCE3 and PcCCE5 , which were significantly upregulated in spirodiclofen-resistant strain and after exposure to spirodiclofen. RNA interference of PcCCE3 and PcCCE5 increased the spirodiclofen susceptibility in P. citri . In vitro metabolism indicated that Pc CCE3 and Pc CCE5 could interact with spirodiclofen, but metabolites were detected only in the Pc CCE3 treatment. Our results indicated that Pc CCE3 participates in spirodiclofen resistance through direct metabolism, and Pc CCE5 may be involved in the spirodiclofen resistance by passive binding and sequestration, which provides new insights into spirodiclofen resistance in P. citri .

A novel series of benzenesulfonamide substituted spirothiazolidinone derivatives (3a-j) were synthesized, characterized and evaluated for their antiviral activity. The spirocyclic compounds were prepared by the condensation of 4-(aminosulfonyl)-2-methoxybenzohydrazide, appropriate cyclic ketones and 2-mercaptopropionic acid in a one-pot reaction. The structures of the new compounds were established by IR, 1 H NMR, 13 C NMR (APT), and elemental analysis. The new compounds were evaluated in vitro antiviral activity against influenza A/H1N1, A/H3N2 and B viruses, as well as herpes simplex virus type 1 (HSV-1), respiratory syncytial virus (RSV) and yellow fever virus (YFV). Two derivatives bearing propyl (3d) and tert-butyl (3e) substituents at position 8 of the spiro ring exhibited activity against influenza A/H1N1 virus with EC50 values in the range of 35-45 µM and no cytotoxicity at 100 μM, the highest concentration tested., (© 2024. The Author(s).)

Imatinib mesylate was the first representative BCR-ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR-ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR-ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS-1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino-pyrimidine-pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro-oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC 50 of the most active substances was determined to be within 0.8-9.8 µM., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Four new psammaplysin derivatives (1-4) with fatty acyl substituents, designated irciniaplysins A-D, and three known psammaplysins (5-7) were isolated from a marine sponge Ircinia sp. Their structures were elucidated using extensive spectroscopic analyses. The positions of the double bonds and the branch points of the fatty acyl side chains were determined by GC-MS analysis of their fatty acid methyl ester (FAME) derivatives. Irciniaplysins A (1) and B (2) contained an unusual long-chain fatty acyl substituent with a 5,9-diene unit. The isolated compounds were evaluated for their cytotoxic activity against the human colorectal carcinoma (HCT 116) cells, however, none of these compounds showed significant activity., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

A new spiroterpenoid, namely tinctorin ( 1 ), along with one known compound, norreticulatin ( 2 ), were isolated from the lichen Parmotrema tinctorum (Despr. ex Nyl.) Hale. Their structures were elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. The absolute configuration of 2 was established for the first time. Compound 1 was evaluated for its inhibitory activity against α- glucosidase and found to be inactive.

With climate change, the spotted-wing Drosophila (SWD, Drosophila suzukii) invades a great number of fruit production regions worldwide. A plethora of insecticides are being applied for management of this pest. As expected, SWD develops resistance against some potent insecticides or is rather insensitive to some others. Therefore, there is an urgent need to identify and characterize alternative insecticides to control SWD populations. Here, we have studied the effects of the orally applied inhibitor of the fatty acid synthesis pathway spirotetramat on SWD fitness with respect to fecundity and surface barrier function at different stages. In our experiments, we applied spirotetramat mixed with baker's yeast and showed that females and males were not repelled by effective concentrations of this insecticide. We found that spirotetramat, by trend, lowers egg numbers laid by fed females. These eggs rapidly desiccate, and only a few larvae hatch. Spirotetramat is lethal to larvae and reduces survival of adult flies under low-humidity conditions. Taken together, based on our data, we propose to use yeast supplemented with spirotetramat and additional SWD-specific attractants in traps in non-crop areas in order to eradicate SWD populations before they infest crop production sites., (© 2023 The Authors. Insect Science published by John Wiley & Sons Australia, Ltd on behalf of Institute of Zoology, Chinese Academy of Sciences.)

Spiro-5-nitro isatino aza-β-lactams were produced by a [2 + 2] cycloaddition of 5-nitro isatin Schiff bases [1-5] with different aromatic isocyanate and thioisocyanate. 1HNMR and 13CNMR as well as FTIR spectroscopies, were used to identify the structures of the obtained compounds. These spiro-5-nitro isatin aza- β-lactams interest to us due to their potential antioxidant and anticancer properties. The MTT assay was used to examine in vitro bioactivity testing against breast cancer (MCF-7) cell lines. From result data, compound 14 displayed IC50 values that were lower than those of the clinically used anticancer drug tamoxifen toward MCF-7 cells after 24 h while compound 9 after 48 h synthesized compounds [6-20] were evaluated for against antioxidant activity by using DPPH assay. In molecular docking, Promising compounds were used to reveal potential cytotoxic activity mechanisms.

Highly functionalized spirobisnaphthalenes, preussomerins N ( 1 ) and O ( 2 ), and simpler compounds, such as 2,3-α-epoxypalmarumycin CP 18 ( 3 ), 3α-hydroxy-CJ-12,372 ( 4 ), and 16 known structurally related congeners, were isolated from a culture broth of Roussoella sp. KT4147. Structural analysis revealed that 1 was a dimer of preussomerin G ( 6 ), connected by a nitrogen atom, and 2 was a derivative of 6 with a macommelin substructure. Preussomerin N ( 1 ) was considered to be biosynthetically derived via the Michael-type 1,4-addition of ammonia to 6 , followed by another Michael addition to another molecule of 6 . Contrarily, 2 was suggested to be derived through an endo -Diels-Alder cycloaddition between a diene derived from the ( E )-enol form of macommelinal via an ene -reaction and dienophile 6 . Compounds 1 and 2 exhibited potent cytotoxicity against COLO-201 human colorectal cancer cells.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John's wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium . Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of -7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium , Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens.

We recently developed a series of nalfurafine analogs (TK10, TK33, and TK35) that may serve as non-addictive candidate analgesics. These compounds are mixed-action agonists at the kappa and delta opioid receptors (KOR and DOR, respectively) and produce antinociception in a mouse warm-water tail-immersion test while failing to produce typical mu opioid receptor (MOR)-mediated side effects. The warm-water tail-immersion test is an assay of pain-stimulated behavior vulnerable to false-positive analgesic-like effects by drugs that produce motor impairment. Accordingly, this study evaluated TK10, TK33, and TK35 in a recently validated assay of pain-related behavioral depression in mice that are less vulnerable to false-positive effects. For comparison, we also evaluated the effects of the MOR agonist/analgesic hydrocodone (positive control), the neurokinin 1 receptor (NK1R) antagonist aprepitant (negative control), nalfurafine as a selective KOR agonist, SNC80 as a selective DOR agonist, and a nalfurafine/SNC80 mixture. Intraperitoneal injection of dilute lactic acid (IP lactic acid) served as a noxious stimulus to depress vertical and horizontal locomotor activity in male and female ICR mice. IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine/SNC80 mixture, or the KOR/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR/DOR agonists as candidate analgesics.

Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.

There is an urgent unmet need for more targeted and effective treatments for advanced epithelial ovarian cancer (EOC). The emergence of drug resistance is a particular challenge, but small molecule covalent inhibitors have promise for difficult targets and appear less prone to resistance. Michael acceptors are covalent inhibitors that form bonds with cysteines or other nucleophilic residues in the target protein. However, many are categorized as pan-assay interference compounds (PAINS) and considered unsuitable as drugs due to their tendency to react non-specifically. Targeting RPN13/ADRM1-mediated substrate recognition and deubiquitination by the proteasome 19S Regulatory Particle (RP) is a promising treatment strategy. Early candidate RPN13 inhibitors (iRPN13) produced a toxic accumulation of very high molecular weight polyubiquitinated substrates, resulting in therapeutic activity in mice bearing liquid or solid tumor models, including ovarian cancer; however, they were not drug-like (PAINS) because of their central piperidone core. Up284 instead has a central spiro-carbon ring. We hypothesized that adding a guanidine moiety to the central ring nitrogen of Up284 would produce a compound, RA475, with improved drug-like properties and therapeutic activity in murine models of ovarian cancer. RA475 produced a rapid accumulation of high molecular polyubiquitinated proteins in cancer cell lines associated with apoptosis, similar to Up284 although it was 3-fold less cytotoxic. RA475 competed binding of biotinylated Up284 to RPN13. RA475 shows improved solubility and distinct pharmacodynamic properties compared to Up284. Specifically, tetraubiquitin firefly luciferase expressed in leg muscle was stabilized in mice more effectively upon IP treatment with RA475 than with Up284. However, pharmacologic analysis showed that RA475 was more rapidly cleared from the circulation, and less orally available than Up284. RA475 shows reduced ability to cross the blood-brain barrier and in vitro inhibition of HERG. Treatment of mice with RA475 profoundly inhibited the intraperitoneal growth of the ID8-luciferase ovarian tumor model. Likewise, RA475 treatment of immunocompetent mice inhibited the growth of spontaneous genetically-engineered peritoneal tumor, as did weekly cisplatin dosing. The combination of RA475 and cisplatin significantly extended survival compared to individual treatments, consistent with synergistic cytotoxicity in vitro. In sum, RA475 is a promising candidate covalent RPN13i with potential utility for treatment of patients with advanced EOC in combination with cisplatin., Competing Interests: RA475 is described in the Johns Hopkins University technology C16365 - ANTI-CANCER “SPIROCYCLIC-GUANIDINE COMPOUNDS” AND USES THERE OF, provisional application filed on May 18, 2020 as U.S. Patent Application No. 63/026,268, inventors Roden RB and Anchoori RK. The study described in this publication utilized compounds manufactured by Up Therapeutics LLC (MTA A36130) and covered by US patent US20190365726 and application 17/154,306. Dr. Roden is a consultant to Up Therapeutics LLC and owns stock in the company. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Anchoori is the founder of Up Therapeutics LLC and owns stock in the company. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Michelle Rudek reports a relationship with Geminus Therapeutics, LLC, that includes co-founder, board membership, and equity or stocks. Michelle Rudek reports a relationship with GlaxoSmithKline that includes employment (spouse). This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Anchoori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Greenhouse whitefly (Trialeurodes vaporariorum) is a major global pest, causing direct damage to plants and transmitting viral plant diseases. Management of T. vaporariorum is problematic because of widespread pesticide resistance, and many greenhouse growers rely on biological control agents to regulate T. vaporariorum populations. However, these are often slow and vary in efficacy, leading to subsequent application of chemical insecticides when pest populations exceed threshold levels. Combining chemical and biological pesticides has great potential but can result in different outcomes, from positive to negative interactions. In this study, we evaluated co-applications of the entomopathogenic fungi (EPF) Beauveria bassiana and Cordyceps farinosa and the chemical insecticide spiromesifen in laboratory bioassays. Complex interactions between the EPFs and insecticide were described using an ecotoxicological mixtures model, the MixTox analysis. Depending on the EPF and chemical concentrations applied, mixtures resulted in additivity, synergism, or antagonism in terms of total whitefly mortality. Combinations of B. bassiana and spiromesifen, compared to single treatments, increased the rate of kill by 5 days. Results indicate the potential for combined applications of EPF and spiromesifen as an effective integrated pest management strategy and demonstrate the applicability of the MixTox model to describe complex mixture interactions., (© 2024. The Author(s).)

As a typical RNA virus, the genetic information on HIV-1 is entirely stored in RNA. The reverse transcription activity of HIV-1 reverse transcriptase (RT) plays a crucial role in the replication and transmission of the virus. Non-nucleoside RT inhibitors (NNRTIs) block the function of RT by binding to the RNA binding site on RT, with very few targeting viral RNA. In this study, by transforming planar conjugated ligands into a spiro structure, we convert classical Ru(II) DNA intercalators into a nonintercalator. This enables selective binding to HIV-1 transactivation response (TAR) RNA on the outer side of nucleic acids through dual interactions involving hydrogen bonds and electrostatic attraction, effectively inhibiting HIV-1 RT and serving as a selective fluorescence probe for TAR RNA.

Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200 mg of itraconazole, a strong CYP3A4 inhibitor, on 360 mg of sotorasib PKs. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600 mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960 mg of sotorasib PKs was interrogated after a single dose of 600 mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib C max but did lead to a 26% increase in sotorasib AUC inf . CYP3A4 induction decreased sotorasib C max by 35% and AUC inf by 51%. OATP1B1/3 inhibition decreased sotorasib C max and AUC inf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided., (© 2024, The American College of Clinical Pharmacology.)

A series of 21 new 7'H-spiro[azetidine-3,5'-furo [3,4-d]pyrimidine]s substituted at the pyrimidine ring second position were synthesized. The compounds showed high antibacterial in vitro activity against M. tuberculosis . Two compounds had lower minimum inhibitory concentrations against Mtb (H37Rv strain) compared with isoniazid. The novel spirocyclic scaffold shows excellent properties for anti-tuberculosis drug development., Competing Interests: The authors declare no conflicts of interest.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective dopamine receptor subtype 4 (D 4 R) antagonists not previously reported as potential adjuvants for PD management. In this study, a library screening and artificial neural network quantitative structure-activity relationship (QSAR) modeling with experimentally driven library design resulted in a class of spirocyclic compounds to identify candidate D 4 R antagonists. However, developing selective D 4 R antagonists suitable for clinical translation remains a challenge.

A series of spirocyclopropyl oxindoles with benzimidazole substitutions was synthesized and tested for their cytotoxicity against selected human cancer cells. Most of the molecules exhibited significant antiproliferative activity with compound 12 p being the most potent. It exhibited significant cytotoxicity against MCF-7 breast cancer cells (IC 50 value 3.14±0.50 μM), evidenced by the decrease in viable cells and increased apoptotic features during phase contrast microscopy, such as AO/EB, DAPI and DCFDA staining studies. Compound 12 p also inhibited cell migration in wound healing assay. Anticancer potential of 12 p was proved by the inhibition of tubulin polymerization with IC 50 of 5.64±0.15 μM. These results imply the potential of benzimidazole substituted spirocyclopropyl oxindoles, notably 12 p, as cytotoxic agent for the treatment of breast cancer., (© 2024 Wiley-VCH GmbH.)

Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23 , showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.

Habitat manipulation such as intercropping can be used as a simple and common cultural practice in pest management. This method is based on the principle of reducing pest populations by increasing the diversity of an ecosystem. This study has been carried out to evaluate the influence of additive series intercropping common bean with some aromatic plants (AP), and 2 acaricides on the different life stages (egg, immature mobile stages, and adult) of Tetranychus urticae Koch (Trombidiformes: Tetranychidae), over 2 yr of experimentation (2020 and 2021). This experiment was conducted following a randomized complete block design with 7 treatments including common bean monoculture, common bean sprayed by spiromesifen or Dayabon, and common bean + companion plants (coriander, ajwain, basil, or dill). Each treatment was replicated 3 replicates. The lowest and highest number of eggs, immature mobile stages, and adults were observed in common bean + spiromesifen and the common bean monoculture, respectively. Additionally, the common bean + Dayabon supported significantly different T. urticae life stage densities compared to common bean monoculture. Also, among intercropped treatments, common bean + basil showed the lowest number of T. urticae (eggs, immature mobile stages, and adults). The highest yield and land equivalent ratio were recorded in common bean + basil and common bean + spiromesifen, respectively. Finally, it can be concluded that additive intercropping with these AP can effectively decrease the T. urticae population density, which is useful for the safe production of common bean., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cyclin-dependent kinase 2 (CDK2) regulates cell cycle checkpoints in the synthesis and mitosis phases and plays a pivotal role in cancerous cell proliferation. The activation of CDK2, influenced by various protein signaling pathways, initiates the phosphorylation process. Due to its crucial role in carcinogenesis, CDK2 is a druggable hotspot target to suppress cancer cell proliferation. In this context, several studies have identified spirooxindoles as an effective class of CDK2 inhibitors. In the present study, three spirooxindoles (SOI1, SOI2, and SOI3) were studied to understand their inhibitory mechanism against CDK2 through a structure-based approach. Molecular docking and molecular dynamics (MD) simulations were performed to explore their interactions with CDK2 at the molecular level. The calculated binding free energy for the spirooxindole-based CDK2 inhibitors aligned well with experimental results regarding CDK2 inhibition. Energy decomposition (ED) analysis identified key binding residues, including I10, G11, T14, R36, F82, K89, L134, P155, T158, Y159, and T160, in the CDK2 active site and T-loop phosphorylation. Molecular mechanics (MM) energy was identified as the primary contributor to stabilizing inhibitor binding in the CDK2 protein structure. Furthermore, the analysis of binding affinity revealed that the inhibitor SOI1 binds more strongly to CDK2 compared to the other inhibitors under investigation. It demonstrated a robust interaction with the crucial residue T160 in the T-loop phosphorylation site, responsible for kinase activation. These insights into the inhibitory mechanism are anticipated to contribute to the development of potential CDK2 inhibitors using the spirooxindole scaffold.

Among the many neglected tropical diseases, leishmaniasis ranks second in mortality rate and prevalence. In a previous study, acridine derivatives were synthesized and tested for their antileishmanial activity against L. chagasi. The most active compound identified in that study (1) showed a single digit IC 50 value against the parasite (1.10 μg/mL), but its macromolecular target remained unknown. Aiming to overcome this limitation, this work exploited inverse virtual screening to identify compound 1's putative molecular mechanism of action. In vitro assays confirmed that compound 1 binds to Leishmania chagasi pteridine reductase 1 (LcPTR1), with moderate affinity (Kd=33,1 μM), according to differential scanning fluorimetry assay. Molecular dynamics simulations confirm the stability of LcPTR1-compound 1 complex, supporting a competitive mechanism of action. Therefore, the workflow presented in this work successfully identified PTR1 as a macromolecular target for compound 1, allowing the designing of novel potent antileishmanial compounds., (© 2024 Wiley-VCH GmbH.)

A novel series of 5'-benzylidene-3'-phenylspiro[indoline-3,2'-thiazolidine]-2,4'(1H)-diones 6a-d and spiro[indoline-3,2'-thiazolo[5,4-e]pyrimido[1,2-a]pyrimidin]-2(1H)-one 9a-d derivatives have been synthesized. All the newly synthesized compounds were evaluated for antifungal and anti-candidiasis activity by using Disc Diffusion and Modified Microdilution methods. The antimicrobial experiments have shown that the synthesized compounds demonstrated broad-spectrum antifungal activity in vitro. Among them, compounds 9a-9d had stronger antifungal activity against Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans; compounds 6a-d also showed significant antifungal activity against selected fungal strains as compared to ketoconazole, the reference antifungal drug. The evaluation of antifungal activity against drug-resistant fungal variants showed that the designed compounds had significant antifungal activity against the tested variants. The combination of compounds (6a-d) and (9a-d) exhibited that the synthesized compounds had synergistic effects or additive effects. These results demonstrated that the synthesized compounds were putative chitin synthase inhibitors exhibiting broad spectrum antifungal activities. The present results indicate that novel spiro pyrimidine derivatives can be used as an active pharmaceutical ingredient for novel drug candidate for treatment of dermatophytosis and other fungal agents.

A series of spiro β-Lactams (4 a-c, 7 a-c) and thiazolidinones (5 a-c, 8 a-c) possessing 1,8-naphthyridine moiety were synthesized in this study. The structure of the newly synthesized compounds has been confirmed by IR, 1 H-NMR, 13 C NMR, mass spectra, and elemental analysis. The synthesized compounds were tested in vitro for their antibacterial and antifungal activity against various strains. The antimicrobial data showed that most of the compounds displayed good efficacy against both bacteria and fungi. The structure-activity relationship (SAR) studies suggested that the presence of electron-withdrawing chloro (3 b, 4 b, and 5 b) and nitro groups (7 b, 8 b) at the para position of the phenyl ring improved the antimicrobial activity of the compounds. The free radical scavenging assay showed that all the synthesized compounds exhibited significant antioxidant activity on DPPH. Compounds 8 b (IC 50 =17.68±0.76 μg/mL) and 4 c (IC 50 =18.53±0.52 μg/mL) showed the highest antioxidant activity compared to ascorbic acid (IC 50 =15.16±0.43 μg/mL). Molecular docking studies were also conducted to support the antimicrobial and SAR results., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

This article reports one-pot synthesis of ten novel spirooxindoles using 5-methyl-2-thiohydantoin, isatin derivatives, and malononitrile in good to high yields (65-90 %). The structures of the synthesized compounds were deduced by 1 H-NMR, 13 C NMR, FT-IR, and Mass spectral data. The antibacterial activity of the compounds was evaluated against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) based on the Kirby-Bauer method. According to the obtained data, the synthesized compounds show more activity against Gram-positive bacteria than Gram-negative bacteria. Also, the antioxidant activity of these compounds was measured using the DPPH radical scavenging test method, which showed good to excellent activity (59.65-94.03 %). Among them, the chlorinated derivatives (4 f-j) exhibited more antioxidant activity (84.85-94.03 %) than the other compounds (4 a-e) (56.65-74.4 %) and even ascorbic acid as a standard antioxidant compound (82.3 %)., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The citrus red mite, Panonychus citri, is one of the most notorious and devastating citrus pests around the world that has developed resistance to multiple chemical acaricides. In previous research, we found that spirodiclofen-resistant is related to overexpression of P450, CCE, and ABC transporter genes in P. citri. However, the regulatory mechanisms of these detoxification genes are still elusive. This study identified all hormone receptor 96 genes of P. citri. 8 PcHR96 genes contained highly conserved domains. The expression profiles showed that PcHR96h was significantly upregulated in spirodiclofen resistant strain and after exposure to spirodiclofen. RNA interference of PcHR96h decreased expression of detoxification genes and increased spirodiclofen susceptibility in P. citri. Furthermore, molecular docking, heterologous expression, and drug affinity responsive target stability demonstrated that PcHR96h can interact with spirodiclofen in vitro. Our research results indicate that PcHR96h plays an important role in regulating spirodiclofen susceptibility and provides theoretical support for the resistance management of P. citri., Competing Interests: Declaration of competing interest The author declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Four compounds (1-4) featuring with an L -rhodinose and spiroketal, possess uncommon continuous hydroxy groups in the macrolide skeleton, and a dichloro-diketopiperazine (5) were isolated from a marine derived Micromonospora sp. FIMYZ51. The determination of the relative and absolute configurations of all isolates was achieved by extensive spectroscopic analyses, single-crystal X-ray diffraction analysis, and ECD calculations. According to structural characteristic and genomic sequences, a plausible biosynthetic pathway for compound 1-4 was proposed and a spirocyclase was inferred to be responsible for the formation of the rare spirocyclic moiety. Compounds 1-4 exhibited potent antifungal activities which is equal to itraconazole against Aspergillus niger. Compounds 1-5 exhibited different degree of inhibitory activities against opportunistic pathogenic bacteria of endocarditis (Micrococcus luteus) with MIC values ranging from 0.0625 μg/mL to 32 μg/mL. Compounds 2 and 3 showed moderate cytotoxicity against drug-resistant tumor cell lines (Namalwa and U266). The result not only provides active lead-compounds, but also reveal the potential of the spirocyclase gene resources from Micromonospora sp., which highlights the promising potential of the strain for biomedical applications., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2023. Published by Elsevier B.V.)

Environment-benign, multicomponent synthetic methodologies are vital in modern pharmaceutical research and facilitates multi-targeted drug development via synergistic approach. Herein, we reported green and efficient synthesis of pyrano[2,3-c]pyrazole fused spirooxindole linked 1,2,3-triazoles using a tea waste supported copper catalyst (TWCu). The synthetic approach involves a one-pot, five-component reaction using N-propargylated isatin, hydrazine hydrate, ethyl acetoacetate, malononitrile/ethyl cyanoacetate and aryl azides as model substrates. Mechanistically, the reaction was found to proceed via in situ pyrazolone formation followed by Knoevenagel condensation, azide alkyne cycloaddition and Michael's addition reactions. The molecules were developed using structure-based drug design. The primary goal is to identifying anti-oxidant molecules with potential ability to modulate α-amylase and DPP4 (dipeptidyl-peptidase 4) activity. The anti-oxidant analysis, as determined via DPPH, suggested that the synthesized compounds, A6 and A10 possessed excellent anti-oxidant potential compared to butylated hydroxytoluene (BHT). In contrast, compounds A3, A5, A8, A9, A13, A15, and A18 were found to possess comparable anti-oxidant potential. Among these, A3 and A13 possessed potential α-amylase inhibitory activity compared to the acarbose, and A3 further emerged as dual inhibitors of both DPP4 and α-amylase with anti-oxidant potential. The relationship of functionalities on their anti-oxidant and enzymatic inhibition was explored in context to their SAR that was further corroborated using in silico techniques and enzyme kinetics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bafilomycins are macrocyclic polyketides with intriguing structures and therapeutic value. Genomic analysis of Streptomyces sp. SCSIO 66814 revealed a type I polyketide synthase biosynthetic gene cluster (BGC), namely blm, which encoded bafilomycins and featured rich post-modification genes. The One strain many compounds (OSMAC) strategy led to the discovery of six compounds related to the blm BGC from the strain, including two previously undescribed 6,6-spiroketal polyketides, streptospirodienoic acids D (1) and E (2), and four known bafilomycins, bafilomycins P (3), Q (4), D (5), and G (6). The structures of 1 and 2 were determined by extensive spectroscopic analysis, quantum calculation, and biosynthetic analysis. Additionally, the absolute configurations of the 6/5/5 tricyclic ring moiety containing six consecutive chiral carbons in the putative structures of 3 and 4 were corrected through NOE analysis, DP4+ calculation, and single-crystal X-ray diffraction data. Bioinformatic analysis uncovered a plausible biosynthetic pathway for compounds 1-6, indicating that both streptospirodienoic acids and bafilomycins were derived from the same blm BGC. Additionally, sequence analysis revealed that the KR domains of module 2 from blm BGC was B1-type, further supporting the configurations of 1-4. Notably, compounds 3 and 4 displayed significant cytotoxic activities against A-549 human non-small cell lung cancer cells and HCT-116 human colon cancer cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Compound 1 is formed by a microwave-assisted multicomponent reaction of 1-methylpiperidin-4-one, 2-amino-4-methoxy-6-methyl-1,3,5-triazine, and thiosemicarbazide, followed by the synthesis of Schiff base 2a-l with a variety of aldehydes. A comparison was made between the conventional and microwave methods, and the microwave approach was shown to be considerably superior to the classical method since it takes less time and produces higher yields. Several spectral investigations, including 1 H NMR, 13 C NMR, Mass, and IR spectroscopy, are used to characterize the complete series. In vitro antibacterial testing suggests that compounds 2c, 2f, and 2g are promising antibacterial agents, although compounds 2d, 2e, and 2l are effective antimycobacterial agents when compared to the conventional medicine Rifampicin. The docking score from docking studies is considerable, which validates the results of the biological examination. Molecular docking was performed on Escherichia coli DNA gyrase. According to the in silico ADME analysis, each drug molecule is ideal for use in terms of drug solubility, hydrogen bonding, and cell permeability., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Two undescribed cladosporol derivatives, cladosporols J-K (1-2), and three previously unreported spirobisnaphthalenes, urnucratins D-F (3-5), as well as eleven known cladosporols (6-16), were characterized from Cladosporium cladosporioides (Cladosporiaceae), a common plant pathogen isolated from the skin of Chinese toad. Cladosporols J-K (1-2) with a single double bond have been rarely reported, while urnucratins D-F (3-5) featured an unusual benzoquinone bisnaphthospiroether skeleton, contributing to an expanding category of undiscovered natural products. Their structures and absolute configurations were determined using extensive spectroscopic methods, including NMR, HRESIMS analyses, X-ray single crystal diffraction, as well as through experimental ECD analyses. Biological assays revealed that compounds 1 and 2 exhibited inhibitory activity against A549 cells, with IC 50 values of 30.11 ± 3.29 and 34.32 ± 2.66 μM, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli., Significance: SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL., (© 2024 The Authors; Published by the American Association for Cancer Research.)

δ opioid receptors (DORs) hold potential as a target for neurologic and psychiatric disorders, yet no DOR agonist has proven efficacious in critical phase II clinical trials. The exact reasons for the failure to produce quality drug candidates for the DOR are unclear. However, it is known that certain DOR agonists can induce seizures and exhibit tachyphylaxis. Several studies have suggested that those adverse effects are more prevalent in delta agonists that share the (+)-4-[( αR )- α -((2 S ,5 R )-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N , N -diethylbenzamide (SNC80)/4-[( αR *)- α -((2 S *,5 R *)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl]- N , N -diethylbenzamide chemotype. There is a need to find novel lead candidates for drug development that have improved pharmacological properties to differentiate them from the current failed delta agonists. Our objective in this study was to identify novel DOR agonists. We used a β -arrestin assay to screen a small G-protein coupled receptors (GPCR)-focused chemical library. We identified a novel chemotype of DOR agonists that appears to bind to the orthosteric site based of docking and molecular dynamic simulation. The most potent agonist hit compound is selective for the DOR over a panel of 167 other GPCRs, is slightly biased toward G-protein signaling and has anti-allodynic efficacy in a complete Freund's adjuvant model of inflammatory pain in C57BL/6 male and female mice. The newly discovered chemotype contrasts with molecules like SNC80 that are highly efficacious β -arrestin recruiters and may suggest this novel class of DOR agonists could be expanded on to develop a clinical candidate drug. SIGNIFICANCE STATEMENT: δ opioid receptors are a clinical target for various neurological disorders, including migraine and chronic pain. Many of the clinically tested delta opioid agonists share a single chemotype, which carries risks during drug development. Through a small-scale high-throughput screening assay, this study identified a novel δ opioid receptor agonist chemotype, which may serve as alternative for the current analgesic clinical candidates., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)