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M‐HAT isomerization is a highly reliable method to access thermodynamically stable alkenes with high functional group tolerance. However, synthesis of heteroatom‐substituted alkenes by M‐HAT isomerization reaction is still underdeveloped. Herein, we report an enamide synthesis using M‐HAT via a combination of cobalt and photoredox catalysis. This method tolerates a variety of functional groups including haloarenes, heteroarenes, free hydroxy groups, non‐protected indoles, and drug derivatives. Furthermore, this method can isomerize styrene derivatives in good yield and E/Z selectivity. [ABSTRACT FROM AUTHOR]

The proposed article relates to synthesis and the study of new propargyl ester derivatives, and biostimulation activity of 4-(bis(2- hydroxyethyl)amino)but-2-yn-1-yl butyrate. Aminomethylation reactions of the obtained propargyl ester with ethanolamine and paraform were carried out in the presence of a catalyst. Copper salts were used as a catalyst. The structure of the new propargyl ester derivatives was established by IR and ¹H-, 13C- NMR spectroscopy. Comparative tests show that the test derivative of the drug 4-(bis(2- hydroxyethyl)amino)but-2-yn-1-yl butyrate showed a higher growth-promoting activity. [ABSTRACT FROM AUTHOR]

Metformin is a versatile, biocompatible, and cheap bis‐guanidine used as first response line in the type II diabetes treatment. Since its first human trials (1956) several structural modifications were carried out to increase its activity. However, with this augmented activity, the biological compatibility diminishes, generating serious side effects, such as lactic acidosis. Considering that cytochrome P450 oversees the metformin metabolism and its weakness to eliminate fluorinated metabolites; we envisioned the synthesis of benzyl fluorinated metformin derivatives. In our hypothesis the fluorine atoms can give, by inductive effect, a higher acidity to the hydrogen in the benzylic nitrogen, increasing its solubility. On the other hand, fluorine would give resistance to cP450 allowing the molecule acting longer. Thus, a family of fourteen fluorobenzyl metformins were synthesized and characterized, then an in vitro enzymatic assay with α‐amylase was performed to select the five best performing compounds, then an in vivo experiment was carried out with streptozotocin‐induced CD1 mice using the selected derivatives. Blood glucose was measured every day. After sacrifice, the lipid profile, serum, and liver γ‐glutamyl transferase (GGT) activity determined the biocompatibility. Results showed two compounds (1 L and 1 M) with enhanced activity and higher biocompatibility for blood glucose, lipids metabolism and GGT activity regulation. [ABSTRACT FROM AUTHOR]

1‐Aryl‐substituted bicyclo[1.1.1]pentanes (BCPs) are an important class of BCP derivatives with widespread application in drug development. Most syntheses of these materials require multiple chemical steps via BCP electrophiles or nucleophiles derived from [1.1.1]propellane. Although one‐step, multicomponent radical cross‐coupling reactions could provide a more sustainable and rapid route to access diverse heteroarylated BCPs, current approaches are limited to tertiary alkyl radicals, leading to a decrease in their practical value. In this study, a conceptually different approach enabled by a radical multicomponent heteroarylation of [1.1.1]propellane to access functionalized heteroarylated BCPs is described. Importantly, this protocol is compatible with primary‐, secondary‐, and tertiary aliphatic radicals, as well as various fluoroalkyl radical sources, thus enabling rapid library generation of sought‐after BCP derivatives for drug development. [ABSTRACT FROM AUTHOR]

Aggregates of the antioxidant superoxide dismutase 1 (SOD1) are one of the major contributors to the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in SOD1 lead to an unstable structure and aggregation that perturbs the balance of reactive oxygen species in cells. Oxidation damage to the solvent‐exposed Trp32 also causes aggregation of SOD1. Here, the FDA‐approved antipsychotic drug paliperidone is identified to interact with Trp32 of SOD1 by structure‐based pharmacophore mapping and crystallographic studies. Paliperidone is used for the treatment of schizophrenia. The crystal structure of the complex with SOD1, refined to 2.1 Å resolution, revealed that the ligand binds to the SOD1 β‐barrel in the β‐strand 2 and 3 regions, which are known to scaffold SOD1 fibrillation. The drug also makes substantial π–π interaction with Trp32. Microscale thermophoresis studies confirm significant binding affinity of the compound, suggesting that the ligand can inhibit or prevent tryptophan oxidation. Thus, the antipsychotic drug paliperidone or a derivative may avert SOD1 aggregation and can be used as a lead for ALS drug development. [ABSTRACT FROM AUTHOR]

Escherichia coli is presented in the human intestines as a harmless bacterium, but if it exceeds the normal threshold, it will be pathogenic bacteria causing other pathogens to grow faster; there are also subspecies, each of which causes a different disease, such as intestinal or urinary infections, which can be severe. A theoretical study on the Kaempferol derivative compounds, which belongs to the flavonoids extracted from Senna Alexandrina plant as part of medicinal plant-based drugs and five other derivatives (collected according to literature) against Escherichia coli UDPMurNAc-tripeptide d-alanyl-d-alanine-adding enzyme (MurF) as a therapeutic target. The antibacterial effect of Senna alexandrina was studied using computational molecular docking to investigate the interaction type between Kaempferol derivatives and MurF. In addition, molecular dynamics simulation for M1-Kaempferol derivative and MurF complex show high stability over time (0–100 ns). The toxicity of Kaempferol derivative as a potential drug was determined by ADME-Tox profile for M1-Kaempferol derivative to show their ability to intervene in an antibacterial drug. [ABSTRACT FROM AUTHOR]

Strategies for the preparation of sulfones have received much attention because they have found widespread applications in the pharmaceutical, agrochemical, and materials science fields. Although the radical hydrosulfonylations of alkenes have provided a direct and powerful technique for sulfone synthesis, these protocols still suffer from some shortcomings, such as a limited alkene scope and the use of expensive photocatalysts and/or 4-mercaptophenol. Herein, we report a visible light-initiated manganese-catalyzed radical hydrosulfonylation technique using commercially available and relatively cheap sulfonyl chlorides as sulfonyl radical sources, which can expediently convert a wide range of alkenes to valuable sulfonyl-containing compounds under very mild reaction conditions. Besides a broad substrate scope (we disclose more than 50 examples), this practical strategy exhibits extraordinary functional-group tolerance and can be applied to the late-stage functionalization of complex drug derivatives. Importantly, compared to the existing methods for the photocatalytic hydrosulfonylation of alkenes, the current procedure avoids the usage of precious Ir-based photocatalysts and toxic 4-mercaptophenol, thus providing a green and sustainable alternative to alkene hydrosulfonylation. [ABSTRACT FROM AUTHOR]

Introduction: The local peripheral combination of analgesic drugs with herbal derivatives may have beneficial effects. Information on the action mechanism of these interactions between drugs is scarce. Therefore, the main of the present study was to determine the pharmacological interaction and action mechanism of the combination α-Bisabolol and diclofenac. Methods: Rats were injected in the dorsal surface of the right hind paw with 1% formalin. Rats received subcutaneous injections in the dorsal surface of paw of vehicles or increasing doses of α-Bisabolol, diclofenac or their combination before formalin injection into the paw. Antinociception of the α-Bisabolol + diclofenac combination was evaluated with and without the local treatment of naloxone, metformin, NG-nitro-L-arginine methyl ester (L-NAME), 1H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ), glibenclamide, glipizide, 4-aminopyridine, tetraethylammonium, apamin, or charybdotoxin. Results: α-Bisabolol, diclofenac or α-Bisabolol-diclofenac combinations produced significant antinociception in the rat (p < 0.05). The experimental effective dose (ED) value of 109.2 μg/paw was different significantly of the theoretical effective dose (ED) of 245.7 μg/paw (synergism). Blockers significantly reverted the antinociception produced by the synergistic combination of α-Bisabolol and diclofenac. Discussion: Data showed a synergism of the α-Bisabolol-diclofenac combination and the activation of the opioid receptor-Nitric Oxide-cyclic GMP-K+ channels pathway and a biguanide-dependent mechanism in order to produce the potentiation of its peripheral antinociception in the formalin test. [ABSTRACT FROM AUTHOR]

Octreotide, a somatostatin analogue, has shown its efficacy for the diagnostics and treatment of various types of cancer, i.e., in octreotide scan, as radio-marker after labelling with a radiopharmaceutical. To avoid toxicity of radio-labeling, octreotide-based assays can be implemented into magnetic resonance techniques, such as MRI and NMR. Here we used a Parahydrogen-Induced Polarization (PHIP) approach as a cheap, fast and straightforward method. Introduction of l-propargyl tyrosine as a PHIP marker at different positions of octreotide by manual Solid-Phase Peptide Synthesis (SPPS) led to up to 2000-fold proton signal enhancement (SE). Cell binding studies confirmed that all octreotide variants retained strong binding affinity to the surface of human-derived cancer cells expressing somatostatin receptor 2. The hydrogenation reactions were successfully performed in methanol and under physiologically compatible mixtures of water with methanol or ethanol. The presented results open up new application areas of biochemical and pharmacological studies with octreotide. [ABSTRACT FROM AUTHOR]

Nintedanib, a potent, oral, small‐molecule tyrosine kinase inhibitor, is known as a triple angiokinase inhibitor, inhibiting three major signaling pathways in angiogenesis. Here, we report full details of the alternative path toward the synthesis of nintedanib via novel intermediates. A key feature of our approach is the stereoselective intramolecular cyclization strategy that enables the concise conversion of β‐keto amide into a 3‐acyloxindole derivative, which is an important scaffold for nintedanib synthesis. Subsequent condensation of oxindole scaffold with synthesized amine derivative led to the drug nintedanib with good yields. [ABSTRACT FROM AUTHOR]

In clinical medicine, heterocyclic rings like imidazolinone-containing drugs have been discovered to have a wide range of applications. Their unique structural features of imidazolinone derivatives have a wide range of significant pharmacological or biological activities. The pharmaceutical companies frequently perform research and exploit their derivatives for drug discovery. In this work, we examined the progress and structural modification of 5-imidazolinone derivatives in the search for effective anticancer agents; these compounds could be promising anticancer agents with better therapeutic potential for the suppression of tumors. However, 5-imidazolinone derivatives showed anti-bacterial, anti-fungal, anti-diabetic, anti-inflammatory and analgesic activities and also exhibited better in silico and in vitro studies respectively. The specified data may be beneficial for future contrivance. [ABSTRACT FROM AUTHOR]

Vanadium-doped zinc sulfide quantum dots complexed with TiO2 have been designed using the sol–gel technique and characterized using analytical techniques, such as X-ray diffraction analysis (XRD), UV–Vis diffuse reflectance spectra (DRS), Fourier transforms Infra Red (FTIR), Brunauer–Emmett–Teller analysis (BET), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), and transmission electron microscopy (TEM). The X-ray diffraction analysis of the composite material showed sharp peaks corresponding to both TiO2 and ZnSQDs. The FTIR analysis exhibits a strong and broad absorption at 807 cm−1 indicating the assimilation of vanadium metal in the ZnSQDs lattice. The DRS spectra showed a bathochromic shift of 25 nm in the synthesized V-ZnSQDs@TiO2 composite compared with the pure sample. The photocatalytic performance of the synthesized composite was tested by studying the degradation of two different chromophoric organic dyes, rhodamine B (RhB), methylene blue (MB) and a drug derivative paracetamol (PCM) in aqueous suspension under UV-light illumination. Among the synthesized materials, the composite (V-ZnSQDs@TiO2) was established to be more active than the pure ZnSQDs, TiO2, and V-ZnSQDs for the degradation of compounds under investigation. The activity of the synthesized catalyst was also tested for the mineralization of all compounds by measuring the depletion in total organic carbon (TOC) at different irradiation times. The results showed that the catalyst degrades the compounds and mineralizes them efficiently. The primary reactive species involved in the photodegradation reaction were determined by quenching studies, terephthalic acid, and NBT probe methods. A probable mechanistic pathway for the decomposition of compounds has been proposed. [ABSTRACT FROM AUTHOR]

Life is chiral, as its constituents consist, to a large degree, of optically active molecules, be they macromolecules (proteins, nucleic acids) or small biomolecules. Hence, these molecules interact disparately with different enantiomers of chiral compounds, creating a preference for a particular enantiomer. This chiral discrimination is of special importance in medicinal chemistry, since many pharmacologically active compounds are used as racemates—equimolar mixtures of two enantiomers. Each of these enantiomers may express different behaviour in terms of pharmacodynamics, pharmacokinetics, and toxicity. The application of only one enantiomer may improve the bioactivity of a drug, as well as reduce the incidence and intensity of adverse effects. This is of special significance regarding the structure of natural products since the great majority of these compounds contain one or several chiral centres. In the present survey, we discuss the impact of chirality on anticancer chemotherapy and highlight the recent developments in this area. Particular attention has been given to synthetic derivatives of drugs of natural origin, as naturally occurring compounds constitute a major pool of new pharmacological leads. Studies have been selected which report the differential activity of the enantiomers or the activities of a single enantiomer and the racemate. [ABSTRACT FROM AUTHOR]

Context: The treatment of epilepsy is associated with the inhibition of γ-aminobutyric acid-aminotransferase (GABA-AT), which suppresses the concentration of a key neurotransmitter GABA. Isosteviol, a natural bioactive molecule, has been reported to possess an anticonvulsant property. In this work, we first reported a series of C-15 fluoro isosteviol analogs which are bearing different functional groups at C-16 to investigate the interactions with GABA-AT by applying molecular docking and molecular dynamic simulation approach. The results revealed that all fluoro isosteviol analogs displayed a greater binding affinity than references vigabatrin, an FDA-approved GABA-AT inactivator, and CPP-115, which has Orphan Drug Designation status, and positioned at the same binding site as references. Furthermore, molecular dynamic (MD) simulation studies on minimum (A1), maximum (E1) binding energy score of fluoro isosteviol analogs, and isosteviol (G1) revealed their stable complex formation in terms of RMSD, RMSF, RG, and hydrogen bond formation. All analogs were found to have drug-like nature, non-toxic, >80% absorption, and the majority tend to penetrate brain-blood-barrier (BBB). The investigations found in this study can help in the development of isosteviol derivatives as drugs for the treatment of epilepsy. Methods: The two-dimensional (2D) ligand structures were drawn using ChembioDraw Ultra 14.0. Molecular docking with Autodock4 and molecular dynamic simulation with GROMACS version 2020.1 were performed. The CHARMM27 all-atom force field was applied for writing the topology. Biovia Discovery Studio DS2021 was used for viewing and analyzing the protein-ligand complexes. The data generated from molecular dynamic simulation trajectories were plotted using the Origin® 8 software. The Open Babel software was utilized for extracting SMILEs files of all the fluoro isosteviol analogs. The drug-likeness and ADMET of the molecules were evaluated by SwissADME and ADMETlab 2.0 web tools. [ABSTRACT FROM AUTHOR]

In recent years, several methods for the direct desaturation of aliphatic compounds have been developed, facilitated by the unique combination of photoredox and transition‐metal catalysis. Hereby, alkenes with high functionalization potential can be prepared in a straightforward fashion. We adapted a previously reported system involving tetrabutylammonium decatungstate (TBADT) as hydrogen atom transfer (HAT) agent and a cobaloxime co‐catalyst for dihydrogen evolution for the dehydrogenative preparation of linear enamides and enecarbamates from saturated precursors. The substrate scope includes several natural products and drug derivatives. The reaction does not require noble metal catalysts, exhibits short reaction times compared to previous methods and is suitable for the late‐stage functionalization of drug derivatives. [ABSTRACT FROM AUTHOR]

Efficient protocols for accessing iodo‐substituted diaryl and aryl(vinyl) sulfides have been developed using iodonium salts as reactive electrophilic arylation and vinylation reagents. The reactions take place under transition‐metal‐free conditions, employing odorless and convenient sulfur reagents. A wide variety of functional groups are tolerated in the S‐diarylation, enabling the regioselective late‐stage application of several heterocycles and drug molecules under mild reaction conditions. A novel S‐difunctionalization pathway was discovered using vinyliodonium salts, which proceeds under additive‐free reaction conditions and grants excellent stereoselectivity in the synthesis of aryl(vinyl) sulfides. A one‐pot strategy combining transition‐metal‐free diarylation and subsequent reduction provided facile access to electron‐rich thioanilines and a direct synthesis of a potential drug candidate derivative. The retained iodo group allows a wide array of further synthetic transformations. Mechanistic insights were elucidated by isolating the key intermediate, and the relevant energy profile was substantiated by DFT calculations. [ABSTRACT FROM AUTHOR]

Amphetamine and cathinone derivatives are abused recreationally due to the sense of euphoria they provide to the user. Methodologies for the rapid detection of the drug derivative present in a seized sample, or an indication of the drug class, are beneficial to law enforcement and healthcare providers. Identifying the drug class is prudent because derivatisation of these drugs, to produce regioisomers, for example, occurs frequently to circumvent global and local drug laws. Thus, newly encountered derivatives might not be present in a spectral library. Employment of benchtop nuclear magnetic resonance (NMR) could be used to provide rapid analysis of seized samples as well as identifying the class of drug present. Discrimination of individual amphetamine‐, methcathinone‐, N‐ethylcathinone and nor‐ephedrine‐derived fluorinated and methylated regioisomers is achieved herein using qualitative automated 1H NMR analysis and compared to gas chromatography–mass spectrometry (GC–MS) data. Two seized drug samples, SS1 and SS2, were identified to contain 4‐fluoroamphetamine by 1H NMR (match score median = 0.9933) and GC–MS (RRt = 5.42–5.43 min). The amount of 4‐fluoroamphetamine present was 42.8%–43.4% w/w and 48.7%–49.2% w/w for SS1 and SS2, respectively, from quantitative 19F NMR analysis, which is in agreement with the amount determined by GC–MS (39.9%–41.4% w/w and 49.0%–49.3% w/w). The total time for the qualitative 1H NMR and quantitative 19F NMR analysis is ~10 min. This contrasts to ~40 min for the GC–MS method. The NMR method also benefits from minimal sample preparation. Thus, benchtop NMR affords rapid, and discriminatory, analysis of the drug present in a seized sample. [ABSTRACT FROM AUTHOR]

Cholinesterases catalyze the breakdown of the neurotransmitter acetylcholine (ACh), a naturally occurring neurotransmitter, into choline and acetic acid, allowing the nervous system to function properly. In the human body, cholinesterases come in two types, including acetylcholinesterase (AChE; E.C.3.1.1.7) and butyrylcholinesterase (BChE; E.C.3.1.1.8). Both cholinergic enzyme inhibitors are essential in the biochemical processes of the human body, notably in the brain. On the other hand, GSTs are found all across nature and are the principal Phase II detoxifying enzymes in eukaryotes and prokaryotes. Specific isozymes are identified as therapeutic targets because they are overexpressed in various malignancies and may have a role in the genesis of other diseases such as neurological disorders, multiple sclerosis, asthma, and especially cancer cell. Piperazine chemicals have a role in many biological processes and have fascinating pharmacological properties. As a result, therapeutically effective piperazine research is becoming more prominent. Half maximal inhibition concentrations (IC50) of piperazine derivatives were found in ranging of 4.59–6.48 µM for AChE, 4.85–8.35 µM for BChE, and 3.94‐8.66 µM for GST. Also, piperazine derivatives exhibited Ki values of 8.04 ± 5.73–61.94 ± 54.56, 0.24 ± 0.03–32.14 ± 16.20, and 7.73 ± 1.13–22.97 ± 9.10 µM toward AChE, BChE, and GST, respectively. Consequently, the inhibitory properties of the AChE/BChE and GST enzymes have been compared to Tacrine (for AChE and BChE) and Etacrynic acid (for GST). [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic is an acute and rapidly evolving global health crisis. To better understand this disease's molecular basis and design therapeutic strategies, we built upon the recently proposed concept of an integrated cell, iCell, fusing three omics, tissue-specific human molecular interaction networks. We applied this methodology to construct infected and control iCells using gene expression data from patient samples and three cell lines. We found large differences between patient-based and cell line-based iCells (both infected and control), suggesting that cell lines are ill-suited to studying this disease. We compared patient-based infected and control iCells and uncovered genes whose functioning (wiring patterns in iCells) is altered by the disease. We validated in the literature that 18 out of the top 20 of the most rewired genes are indeed COVID-19-related. Since only three of these genes are targets of approved drugs, we applied another data fusion step to predict drugs for re-purposing. We confirmed with molecular docking that the predicted drugs can bind to their predicted targets. Our most interesting prediction is artenimol, an antimalarial agent targeting ZFP62, one of our newly identified COVID-19-related genes. This drug is a derivative of artemisinin drugs that are already under clinical investigation for their potential role in the treatment of COVID-19. Our results demonstrate further applicability of the iCell framework for integrative comparative studies of human diseases. [ABSTRACT FROM AUTHOR]

The present study describes synthesis of some new luminol derivatives, which might play an important role in biological active agents. These new synthesized compounds are functionalized based on luminol (LM) with different carboxylic drugs such as mefenamic acid, ibuprofen, diclofenac sodium, and ampicillin). Synthesis processes was conducted by converting carboxylic group in the investigated drugs into acid chloride group by reacting with SOCl2. Then the synthesized chloride drug derivatives were reacted with luminol in presences of DMSO and TEA to yield the final target molecules. These compounds were characterized using FTIR, NMR and CHNS techniques. Besides that, their physical properties and solubility were also investigated. Biological activity of the derivatives (TH1-TH4) was investigated using a pathogenic bacterium, Staphylococcus aureus (gram +ve), and Escherichia (E. coli) (gram -ve). The obtained results for antibacterial activity showed that TH1-TH4 derivatives have higher antibacterial activity against these types of bacteria in comparison with pure LM compound and the investigated drugs. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes Mellitus is a disorder of metabolism described by high glucose levels. The disorder kills a larger number of individuals consistently than of malignant growth and AIDS combined. Presently available drugs have several drawbacks forcing to withdraw from treatment. The potent side effect i.e., hepatotoxicity and cardiovascular toxicity limits the use of thiazolidine-2,4-dione derivative as safe drugs. Our aim is towards the development of synthetic compounds as potential antidiabetic agents, particularly preparation and screening of new analogues of thiazolidine-2,4-dione (TZD) which are well established as oral insulin sensitizing agents that improve insulin resistance and are agonists of Peroxisome Proliferator Activated Receptor-γ (PPAR-γ). Materials and Methods: Proper substitution at C-5 position of thiazolidine-2,4-dione could produce better and potential antidiabetics with improved pharmacological properties, including toxicity. Our aim of this research work is towards this. Results: A series of C-5 substituted thiazolidine-2,4-dione analogues were synthesized. Structures of these new analogues were confirmed by IR, ¹H-NMR and MASS spectroscopy. Among the synthesized compounds, three compounds: 5-(2-pyridinylbenzylidene) thiazolidine-2,4-dione, 5-(3,4-dimethoxybenzylidene) thiazolidine-2,4-dione and 5-(2,3,4-trifluorobenzylidene) thiazolidine-2,4-dione showed significant antidiabetic activity in streptozotocin induced diabetic mice comparable with Pioglitazone drug. The molecular docking studies of these compounds performed using protein target showed amino acid interactions with Leu270, Gln283 and Arg288 similar with that of Rosiglitazone and Pioglitazone. The compounds did not show any toxic effect in mice even at 2000 mg/kg of dose. Therefore, synthesis of modified and better thiazolidine-2,4-dione containing drugs other than the currently available drugs is of importance in antidiabetic drug research. [ABSTRACT FROM AUTHOR]

Protozoan parasites, such as Giardia lamblia and Trichomonas vaginalis, cause the most prevalent infections in humans in developing countries and provoke significant morbidity and mortality in endemic countries. Despite its side-effects, metronidazole is still the drug of choice as a giardiacidal and trichomonacidal tissue-active agent. However, the emergence of metronidazole resistance and its evolved strategies of parasites to evade innate host defenses have hindered the identification and development of new therapeutic strategies against these parasites. Here, we tested five synthesized benzimidazole derivatives as possible drugs for treating giardiasis and trichomoniasis, probing the bifunctional enzyme glucose 6-phosphate dehydrogenase::6-phosphogluconolactone from G. lamblia (GlG6PD::6PGL) and T. vaginalis (TvG6PD::6PGL) as a drug target. The investigated benzimidazole derivatives were H-B2M1, H-B2M2, H2N-BZM6, O2N-BZM7, and O2N-BZM9. The recombinant enzymes were used in inhibition assays, and in silico computational predictions and spectroscopic studies were applied to follow the structural alteration of the enzymes and identify the possible mechanism of inhibition. We identified two potent benzimidazole compounds (O2N-BZM7 and O2N-BZM9), which are capable of inhibiting both protozoan G6PD::6PGL enzymes and in vitro assays with these parasites, showing that these compounds also affect their viability. These results demonstrate that other therapeutic targets of the compounds are the enzymes GlG6PD::6PGL and TvG6PD::6PGL, which contribute to their antiparasitic effect and their possible use in antigiardial and trichomonacidal therapies. [ABSTRACT FROM AUTHOR]

A metal catalyst free approach for regioselective ortho-chlorination of anilines has been developed using a secondary amine as the organocatalyst and sulfuryl chloride as the halogen source under mild conditions. A wide range of substrates were compatible with this catalytic system. In addition, this catalytic protocol has been applied to the efficient synthesis of bioactive compounds and modification of drug derivatives. Further studies indicated that the anionic trichloride species was responsible for the ortho-selectivity. [ABSTRACT FROM AUTHOR]

Most of the known senolytics are anti-cancer drugs or their derivative molecules. However, senolytics derived from the active ingredients of traditional Chinese medicine (TCM) are rarely reported. Here, we identified oridonin as a novel senolytic and further revealed that it might target a class of glutathione S-transferases to activate ROS-p38 signaling and induce apoptosis in senescent cells. [ABSTRACT FROM AUTHOR]

Benzofurans and benzoxepines are key structural elements present in several natural products and medicinally important targets. Here, we describe an easy‐to‐execute strategy for the synthesis of benzofurans and benzoxepines, by employing Claisen rearrangement and ring‐closing metathesis (RCM) as key steps. Amino acid L‐tyrosine and 1,8‐dihydroxy‐anthraquinone were converted into modified oxacycles in good yields. The RCM approach has been used to produce bis‐fused benzofuran, bis‐fused benzoxepine, and unusual α‐amino acid (AAA) derivatives containing heterocyclic units. Unusual AAA derivatives are among the most important source for new peptide drugs and these AAA derivatives containing oxacycles are useful in designing many natural and unnatural products. Bis‐fused benzofuran and bis‐fused benzoxepine derivatives were also synthesized by the application of double Claisen rearrangement and two‐directional RCM as key steps starting with 1,8‐dihydroxy anthraquinone. [ABSTRACT FROM AUTHOR]

The almost empty armamentarium to treat schistosomiasis, a neglected parasitic disorder caused by trematode flatworms of the genus Schistosoma, except Praziquantel (PZQ), urged to find new alternatives to fight this infection. Carbonic Anhydrase from Schistosoma mansoni (SmCA) is a possible new target against this nematode. Here, we propose new PZQ derivatives bearing a primary sulphonamide group in order to obtain hybrid drugs. All compounds were evaluated for their inhibition profiles on both humans and Schistosoma CAs, X-ray crystal data of SmCA and hCA II in adduct with some inhibitors were obtained allowing the understanding of the main structural factors responsible of activity. The compounds showed in vitro inhibition of immature and adult S. mansoni, but further optimisation is required for improved activity. [ABSTRACT FROM AUTHOR]

In this work, we designed, synthesised and biologically investigated a novel series of 14N- and O-phosphorylated tacrine derivatives as potential anti-Alzheimer's disease agents. In the reaction of 9-chlorotacrine and corresponding diamines/aminoalkylalcohol we obtained diamino and aminoalkylhydroxy tacrine derivatives. Next, the compounds were acid to give final products 6-13 and 16-21 that were characterised by ¹H, 13C, 31P NMR and MS. The results of the docking studies revealed that the designed phosphorus hybrids, in theory can bind to AChE and BChE. All compounds exhibited significantly lower AutoDock Vina scores compared to tacrine. The inhibitory potency evaluation was performed using the Ellman's method. The most inhibitory activity against AChE exhibited compound 8 with an IC50 value of 6.11 nM and against BChE 13 with an IC50 value of 1.97 nM and they were 6- and 12-fold potent than tacrine. Compound 19 showed the lack of hepatocytotoxicity in MTT assay. [ABSTRACT FROM AUTHOR]

With rising living standards and environmental awareness, materials-oriented chemical engineering has increasingly transitioned from traditional rough models to more resource-saving and eco-friendly models, providing an avenue for bio-based materials in the drug carrier field. Because of its excellent physical and chemical properties, including high specific surface area, abundant accessible hydroxyl groups, biocompatibility, and degradability, nanocellulose (NC) is an emerging bio-based material that has been widely exploited as biomedical materials. The modification techniques of NC, as well as advancements in the design and applications of drug carriers, were primarily discussed in this study. First, the NC modification methods are described; second, the applications of NC and its derivatives as drug carriers are summarized, focusing on NC-based carrier models, types of loaded therapeutic agents, and controlled release stimulators; and finally, the current challenges of NC in the drug carrier field and the directions of future research are also discussed. Scheme 1. Recent advances in nanocellulose-based drug carriers including modification methods, carrier models, types of loaded therapeutic agents, and controlled release stimulators are comprehensively summarized. [Display omitted] • A comprehensive review of nanocellulose-based carriers is presented. • Surface modification of nanocellulose through various strategies is summarized. • Classification of nanocellulose-based carriers and types of cargo are introduced. • The stimuli-responsive switches of nanocellulose-based carriers are demonstrated. [ABSTRACT FROM AUTHOR]

Despite the vast amounts of research and remarkable discoveries that have been made in recent decades, cancer remains a leading cause of death and a major public health concern worldwide. Gossypol, a natural polyphenolic compound derived from the seeds, roots, and stems of cotton (Gossypium hirsutum L.), was first used as a male contraceptive agent. Due to its diverse biological properties, including antifertility, antiviral, antioxidant, antibacterial, antimalarial, and most notably antitumor activities, gossypol has been the subject of numerous studies. Nevertheless, no systematic review has been performed that analyzes the antineoplastic potential of gossypol and related natural compounds in an organ-specific manner while delineating the molecular mechanisms of action. Hence, we have performed an extensive literature search for anticancer properties of gossypol and their natural derivatives against various types of cancer cells utilizing PubMed, ScienceDirect, Google Scholar, and Scopus. The sources, distribution, chemical structure, and toxicity of gossypol and its constituents are briefly reviewed. Based on emerging evidence, gossypol and related compounds exhibit significant antineoplastic effects against various cancer types through the modulation of different cancer hallmarks and signaling pathways. Additionally, the synergistic activity of gossypol and its derivatives with chemotherapeutic agents has been observed. Our evaluation of the current literature suggests the potential of gossypol and its derivatives as multitargeting drug candidates to combat multiple human malignancies. [ABSTRACT FROM AUTHOR]

Over the past decades, a number of 1,4‐naphthoquinones have been isolated from natural resources and several of naphthoquinone derivatives with diverse structural motif have been synthesized; they possess a multitude of biochemical properties and modulate numerous pharmacological roles that offer new targets for addressing the challenges pertaining to novel drug developments. Among natural naphthoquinones, lapachol, α‐lapachone, β‐lapachone, lawsone, juglone, and plumbagin have been evaluated for its potential as antitrypanosomal activities. The chemotherapeutic drugs available for combating human trypanosomiasis, that is, American trypanosomiasis and African trypanosomiasis caused by Trypanosoma cruzi and Trypanosoma brucei, respectively, and animal tripanosomosis caused by Trypanosoma evansi have a problem of drug resistance and several toxic effect. Therefore, search of alternative effective drug molecules, without toxic effects, have enthused the researchers for searching new drug entity with potential clinical efficacy. In the search for new antitrypanosomal compound, this review focuses on different natural quinones and their synthetic derivatives associated with antitrypanosomal studies. In this context, this review will be useful for the development of new antitrypanosomal drugs mainly based on different structural modification of natural and synthetic naphthoquinones. [ABSTRACT FROM AUTHOR]

Background: Hydroxyethyl Ester of Mefenamic acid (HEMA), which is an available derivative of mefenamic acid (MFA) in the literature, was shown to exert a strong resistance to enzymatic hydrolysis in various buffer solutions as well as in the plasma. However, there are no studies yet that investigate the biological effects of HEMA as a possible active drug in-vivo. This study provides an in-vivo investigation of the efficacy and toxicity of HEMA in comparison to those of a related drug, MFA, that has a similar chemical structure. Methods: Acute toxicity evaluations were conducted in various groups of mice following administration of high equimolar doses of HEMA and MFA and were measured at various parameters including the percentage of catalepsy, seizure score, percentage of clonic-tonic seizure and death, grimace scale score (GSS) and locomotor activity. In addition, the anti-inflammatory and anti-nociceptive effects of HEMA were evaluated in the carrageenan-induced paw edema test and acetic acid-induced writhing test, respectively. Results: The findings of this study revealed that the percentage of catalepsy, clonic-tonic seizure and death as well as seizure and grimace scale scores were lower in mice treated with HEMA than those treated with equimolar doses of MFA. In addition, treatment with HEMA caused a comparable anti-inflammatory activity in the carrageenan-induced paw edema test and a significantly (p<0.05) higher anti-nociceptive effect in the acetic acidinduced writhing test than that of MFA. Conclusion: Results obtained from this study may indicate that HEMA has superior therapeutic advantages for the management of acute and inflammatory events with a less potential risk of neuromuscular adverse effects. [ABSTRACT FROM AUTHOR]

Objective: Traditional chemical synthesis methods are cumbersome and inefficient. In this study, a novel antitumor molecule, 4-(4-(3-((6,7-bis(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)phenyl sulfurofluoridate (P19G1), was identified by screening a library of Erlotinib derivatives synthesized by modular click chemistry, and the antitumor activity and underlying mechanism of P19G1 were further revealed. Methods: A series of Erlotinib derivatives (840 compounds) were synthesized using a modular click-chemistry method, and then the thiazolyl blue (MTT) method was used to screen and evaluate the inhibitory effect of these compounds on the growth and metastasis of A549 lung adenocarcinoma cells. Among them, the compound P19G1 showed the best inhibitory activity. Furthermore, the antitumor activity and mechanism of P19G1 were investigated with in vitro cell biology and in vivo assays in an animal model. Results: In vitro pharmacological studies showed that P19G1 had inhibitory effects on a variety of tumor cell lines with IC50 values in the range of 1 to 5 μM. Moreover, P19G1 significantly inhibited the proliferation and migration of the human lung adenocarcinoma cell line A549 and human colorectal cancer cell line RKO and promoted cell apoptosis. In vivo tumor-bearing mouse model experiments revealed that 50 mg/kg P19G1 effectively inhibited the growth and metastasis of A549 tumors without obvious toxicity to the host. Conclusions: The rapid structural modification of lead compounds using novel modular click-chemistry reactions holds great potential for use in obtaining diverse derivatives for tumor drug screening and development. P19G1 was discovered because of the application of click chemistry in this study, and it is an antitumor candidate molecule worthy of development. [ABSTRACT FROM AUTHOR]

Herein, an electroreductive carboxylation of organic carbon‐halogen bonds (X=Br and Cl) promoted by catalytic amounts of naphthalene as an organic mediator is reported. This transformation proceeds smoothly under mild conditions with a broad substrate scope of 59 examples, affording the valuable and versatile carboxylic acids in moderate to excellent yields without the need of costly transition metal, wasted stoichiometric metal reductants, or sacrificial anodes. Further late‐stage carboxylations of natural product and drug derivatives demonstrate its synthetic utility. Mechanistic studies confirmed the activation of carbon‐halogen bonds via single‐electron transfer and the key role of naphthalene in this reaction. [ABSTRACT FROM AUTHOR]

Tryptanthrin is a golden-yellow, naturally occurring alkaloid that can be obtained from multiple sources and through different synthetic methodologies. This tetracyclic compound displays several relevant biological activities. The potential of this tetracyclic alkaloid has been widely explored, and several researchers have focused their attention on expanding the variety of tryptanthrin derivatives by using a range of synthetic strategies. In this short review, we aim to address recent developments in the synthesis of the tryptanthrin core, as well as the development of new strategies employed by synthetic organic chemists to obtain novel tryptanthrin derivatives with potential biological activity, using different tools from the chemists' toolbox, such as photocatalysis, solvent-free approaches, and multicomponent reactions. [ABSTRACT FROM AUTHOR]

The rising incidence of dengue virus (DENV) infections in the tropical and sub-tropical regions of the world emphasizes the need to identify effective therapeutic drugs against the disease. Repurposing of drugs has emerged as a novel concept to combat pathogens. In this study, we employed a transcriptomics-based bioinformatics approach for drug identification against DENV. Gene expression omnibus datasets from patients with different grades of dengue disease severity and healthy controls were used to identify differentially expressed genes in dengue cases, which were then applied to the query tool of Connectivity Map to identify the inverse gene–disease–drug relationship. A total of sixteen identified drugs were investigated for their prophylactic, virucidal, and therapeutic effects against DENV. Focus-forming unit assay and quantitative RT-PCR were used to evaluate the antiviral activity. Results revealed that five compounds, viz., resveratrol, doxorubicin, lomibuvir, elvitegravir, and enalaprilat, have significant anti-DENV activity. Further, molecular docking studies showed that these drugs can interact with a variety of protein targets of DENV, including the glycoprotein, the NS5 RdRp, NS2B-NS3 protease, and NS5 methyltransferase The in vitro and in silico results, therefore, reveal that these drugs have the ability to decrease DENV-2 production, suggesting that these drugs or their derivatives could be attempted as therapeutic agents against DENV infections. [ABSTRACT FROM AUTHOR]

[Display omitted] • DIF exhibits dual fluorosolvatochromism indicating complex solvent interactions. • Catalán's model highlights the influence of solvent acidity, basicity, and polarizability on DIF's fluorosolvatochromism. • The explicit interaction between DIF and solvent molecules suggests the formation of stable hydrogen-bonded complexes. • Both the biphenyl and salicylate moieties significantly influence DIF's fluorosolvatochromism behavior. • Understanding DIF's behavior may aid in mitigating drug-induced toxicity. Understanding the photochemical behavior of a photosensitive drug through its molecular properties is crucial for assessing potential phototoxicity. In this study, we examine how the molecular microenvironment influences the physicochemical and photochemical properties of Diflunisal (DIF), an organofluorine salicylate derivative drug. To elucidate the photophysical properties of DIF, we employed absorption and fluorescence spectroscopy techniques combined with various DFT-based computational methods. The solvatochromic and fluorescence behaviors of DIF were investigated employing various neat solvents of various polarity and hydrogen bonding (HB) capabilities. The molecular behavior of DIF exhibited mixed fluorosolvatochromism, where a negative fluorosolvatochromism is noted as solvent polarity increases, where DIF exhibited positive fluorosolvatochromism within the examined set of protic polar solvents. These fluorosolvatochromic behaviors suggest that a combination of factors, including solvent polarity, hydrogen bonding capacity, and specific solvation effects, influences the fluorosolvatochromic properties of DIF. To elucidate the impact of specific and non-specific interactions between DIF and solvent on the fluorosolvatochromism of DIF, we utilized Catalán's four empirical scales model. The results revealed that the solvent's acidity, basicity, and polarizability had approximately equivalent and notable impacts on the fluorosolvatochromic behavior of DIF. For a molecular-level explanation of the experimental spectral properties, we employed DFT and TD-DFT/B3LYP/6–31 + G(d) computational methods, incorporating the IEFPCM implicit solvation approach. It is also revealed that the negative fluorosolvatochromism of DIF is attributed to the solvent's impact on the main electronic transition, namely HOMO → LUMO. It is revealed as well that not only the salicylate moiety is affected by the solvent, but also the biphenyl moiety can exhibit a major contribution to the observed behavior. The results presented here offer insights into the photochemical behavior of DIF within various microenvironments at the molecular level. This understanding could inform future endeavors aimed at mitigating induced toxicity and side effects of DIF. [ABSTRACT FROM AUTHOR]

[Display omitted] • The pK a values were alternatively determined using the eco-friendly green RPLC methods. • The agreement between theoretical and experimental data is given by the LSER approach. • The ionization behavior of the compounds was determined by RPLC methods. • Aqueous p K a values were calculated for hydro-organic and micellar solvent-free mixtures. In this study, the green reverse-phase liquid chromatography (RPLC) method was used in addition to the traditional RPLC method to determine the ionization/protonation constants (pK a) of the guanine derivatives ganciclovir, valacyclovir, and valganciclovir. The determination of these values was carried out in binary acetonitrile–water mixtures (for the traditional RPLC method), ethanol–water binary mixtures (for the green RPLC method), and in aqueous solution of a micelle-forming surfactant (for pure micellar chromatography). The pK a values s s p K a of the compounds were calculated using the linear solvation energy relationship (LSER) method in the studied hydro-organic and micellar solvent-free mixtures. Moreover, the UV–Vis spectrophotometric method was used to compare the s s p K a values of ganciclovir, valaciclovir, and valganciclovir obtained in a acetonitrile–water medium using another method. The pK a values ​​of the examined compounds in water were calculated using the linear relationship between the s s p K a values ​​determined in hydroorganic mixtures and some macroscopic values ​​of acetonitrile and ethanol. Additionally, w w p K a values ​​were determined in the micellar solvent-free mobile phase. Subsequently, the w w p K a values calculated by these direct and indirect methods were compared and the agreement between them was excellent. By using the w w p K a value calculated for each compound, the ionization percentages were calculated at different pH (1–12) values with the Henderson-Hasselbalch equation. The environmental impact of the RPLC methods used in this study was assessed using the green metrics tools GAPI and AGREE. The result of the investigation was that the environmental suitability of the green methods is satisfactory. [ABSTRACT FROM AUTHOR]

Two synthetic approaches for 5-thio- d -glucopyranose (5-TDGP) and its pentaacetates were described, focusing on different protective groups such as tert -butyldimethylsilyl and benzoyl employed to protect 3-OH. These protective groups were easily introduced from the beginning and can be removed during transformation from the corresponding mesylate of α- d -glucofuranose to 5,6-episulfide under mild conditions. In addition, a few purification manipulations were required for each approach. More importantly, 5-TDGP can be prepared using the two approaches starting from 200 g of starting material in 66.08 % and 64.4 % overall yields, respectively. [Display omitted] • Synthetic approaches for 5-thioglucose and its pentaacetate was described. • The approaches can be applied to synthesise product in hundreds--grams scale in satisfactory overall yield. • These approaches would have a broad application in the synthesis of 5-TDGP and its derivatives in carbohydrate-based drug discovery. [ABSTRACT FROM AUTHOR]

• A new curcumin derivative, EMBP was synthesized, and crystallized using slow evaporation method. • The structure was elucidated and studied for its geometrical parameters. • Non-covalent contacts, 2-D fingerprint plot, Hirshfeld surfaces, and energy framework analysis have been performed using crystal explorer 17.5 software. • The spectral, optical and thermal properties were also investigated. • In vitro and in silico investigation have been conducted and found to exhibit potential anticancer activity against breast cancer. Overseeing the diverse pharmacological traits of curcumin, a novel monocarbonyl based curcumin derivative (1-(4-ethylbenzoyl)-3, 5-bis ((E)-4-methoxybenzylidene) piperidin-4-one) [EMBP] was synthesized by Claisen-Schmidt condensation and Schotten-Baumann reaction procedures, and diffraction quality crystal was obtained by slow evaporation method. Geometrical parameters were calculated for the grown crystal by using the SCXRD technique. The non-covalent interactions like C H∙∙∙π, π∙∙∙π were visualized by Hirshfeld surfaces analysis. The contribution of various interactions towards the total Hirshfeld surface has been quantified by 2D fingerprint plot. The synthesized material is characterized for various optical and spectral properties through NMR, FT-Raman, FT-IR, UV–Vis, and PL spectra. The thermal stability and melting point of the material have been examined by TG/DTA analysis. The cytotoxic effect on the normal cell line HEK-293 was evaluated, and found that the compound is highly toxic. Anticancer activity on MCF-7 cell line of the compound was assessed and found to exhibit exceptional efficacy against cancerous cells. Results of molecular docking studies and evaluated ADMET properties clearly demonstrate that the synthesized material can be proposed as a promising medication for treating breast cancer but after an extensive biological and pharmaceutical research. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Absorption studies of (E)-2-hydroxy-5-(((4-sulfamoyl phenyl) imino) methyl) benzoic acid with metal clusters (Pt/Ni/Ru) in gas phase and water phase are investigated. • The adsorption energies of 5FSANI-Pt2-Ru (water medium) cluster are the highest absorption energy. • The studies ELF, LOL and RDG were conducted. • In FMO analysis, we observed very low energy gap values. The adsorption of (E)-2-hydroxy-5-(((4-sulfamoyl phenyl) imino) methyl) benzoic acid (5FSANI) on various metal clusters and chemical descriptors was investigated on the basis of the solvation effects by using frontier molecular orbital (FMO), molecular electrostatic potential (MEP), and wave function analyses. In this study two basis sets (mixed basis set) such as cc-pVDZ and Lan-L2DZ with B3LYP functional level were used. The Lan-L2DZ basis set was used for metal atoms and cc-pVDZ basis set was used for other atoms like, C, H, N, S, and O respectively. The adsorption energy of 5FSANI-Pt2-Ru (water) cluster was found to be the highest (−170.78 kcal/mol), whereas the adsorption energy of 5FSANI-Ru3 (water) cluster was found to be the lowest (−11.94 kcal/mol). After the addition of the metal clusters, 5FSANI became more electrophilic, as evidenced by the higher electrophilicity index of all metal-drug systems. The results of this study indicated that the solvents had stronger negative solvation energies. The investigation of non-covalent contacts showed the considerable inter and intra-molecular interactions. Studies such as electron localized function (ELF), localized orbital locator (LOL), and average localized ionization energy (ALIE) confirmed the electron localization and delocalization energies. The metal frontier molecular orbital and the molecular electrostatic potential of the clusters were calculated by using the density functional theory (DFT) method. [ABSTRACT FROM AUTHOR]

• The interaction of drug MNC with DNA was studied. • Predominant groove binding with moderate intercalation was observed. • A binding energy of ≈ 6 kcal was obtained from ITC experiment. • The MNC-DNA binding process is enthalpy driven. Deoxyribonucleic acid (DNA) is a major target in research pertaining to antiviral and anticancer therapies since it is the principal genetic material that controls vital biological functions. The complex relationship between calf thymus DNA (ct-DNA) and 8-Methoxy-3-nitro-2-(4-methoxyphenyl)-2H-chromene (MNC), an anticancer drug derivative of 2-aryl-3-nitro-2H-chromenes, is explored in this work. Using various spectroscopic methods such as fluorescence, circular dichroism (CD), UV–visible, isothermal titration calorimetry (ITC) experiment, and molecular docking calculations, this study elucidates the binding characteristics and affinity between MNC and ct-DNA. Through predominant groove binding and moderate intercalation, MNC demonstrates a complicated binding pattern with DNA at the minor groove, as shown by the UV–Vis spectra and emission-based dye displacement investigations. DNA undergoes a little conformational change that MNC induces, as shown by CD spectroscopy. The thermodynamics parameters such as the binding constant, binding enthalpy, and binding free energy of DNA-MNC interaction, as calculated by the ITC experiment, were approximately ∼ 104 M−1, −26 kcal mol−1, and 6 kcal/mol, respectively. The binding process is enthalpy driven implying a stabilizing contact of MNC with DNA and the entropic penalty (− T Δ S = +20.1 kcal mol−1) points to a reduction in the degree of freedom of movement. The molecular docking investigation also estimates the similar interaction energy and binding locations of MNC with DNA. Interestingly, MNC attaches to the surface of the DNA via electrostatic interactions; a stronger attachment through van der Waals and hydrophobic contacts within the minor groove follows this. These studies are anticipated to provide researchers with important direction for designing new drug molecules for further biomolecular investigations. [Display omitted] [ABSTRACT FROM AUTHOR]

Antiviral medicines to treat COVID-19 are still scarce. Porphyrins and porphyrin derivatives (PDs) usually present broad-spectrum antiviral activity with low risk of resistance development. In fact, some PDs are clinically approved to be used in anti-cancer photodynamic therapy and repurposing clinically approved PDs might be an alternative to treat COVID-19. Here, we characterize the ability of temoporfin, verteporfin, talaporfin and redaporfin to inactivate SARS-CoV-2 infectious particles. PDs light-dependent and –independent effect on SARS-CoV-2 infectivity were evaluated. PDs photoactivation successfully inactivated SARS-CoV-2 with very low concentrations and light dose. However, only temoporfin and verteporfin inactivated SARS-CoV-2 in the dark, being verteporfin the most effective. PDs treatment reduced viral load in infected Caco-2 cells, while not inducing cytotoxicity. Furthermore, light-independent treatment with temoporfin and verteporfin act on early stages of viral infection. Using lipid vehicles as membrane models, we characterized PDs interaction to the viral envelope. Verteporfin presented the lowest IC50 for viral inactivation and the highest partition coefficients (K p) towards lipid bilayers. Curiously, although temoporfin and redaporfin presented similar K p s , redaporfin did not present light-independent antiviral activity, and only temoporfin and verteporfin caused lipid membrane disorder. In fact, redaporfin is located closer to the bilayer surface, while temoporfin and verteporfin are located closer to the centre. Our results suggest that viral envelope affinity, with penetration and destabilization of the lipid bilayer, seems critical to mediate PDs antiviral activity. Altogether, these findings open new avenues for the off-label application of temoporfin and verteporfin in the systemic treatment of COVID-19. [Display omitted] • Photoactivation of clinically approved porphyrin derivatives inactivated SARS-CoV-2. • Temoporfin and verteporfin inactivated SARS-CoV-2 and ZIKV in the dark. • Porphyrin derivatives deep membrane penetration promotes membrane destabilization. • Virus inactivation by porphyrin derivatives depends on membrane destabilization. [ABSTRACT FROM AUTHOR]

Herein, an efficient and facile approach to valuable β‐hydroxy acid derivatives from readily available aryl epoxides and CO2 with high chemo‐ and regioselectivity under mild and sustainable electrochemical conditions is described. This approach showed broad substrate scope and good functional‐group compatibility. In addition to aryl epoxides, four‐ to six‐membered aryl cyclic ethers could all be tolerated in the reaction to provide synthetically useful hydroxy acids with high efficiency. Further late‐stage carboxylation of complex molecules and drug derivatives demonstrated its potential application in the pharmaceutical industry. Mechanistic studies disclosed possible reaction pathways. [ABSTRACT FROM AUTHOR]

Herein, a novel visible-light photocatalytic radical addition–translocation–cyclization (RATC) approach for the efficient synthesis of sulfonyl-containing azacycles is described. The reaction delivers a wide range of monocyclic, bicyclic and polycyclic azacycles by using easily prepared sodium sulfinates and N-homopropargylic amines as starting materials. Instead of the traditionally used toxic tin reagents and thermally hazardous azos in the RATC process, clean, renewable and sustainable visible light combined with a catalytic amount of photosensitizer is used in this process. Moreover, the successful transformation of some drug derivatives further highlights the potential application of this procedure. [ABSTRACT FROM AUTHOR]

The emergence and spread of the mcr-1 gene and its mutants has immensely compromised the efficient usage of colistin for the treatment of drug-resistant Gram-negative bacterial infection in clinical settings. However, there are currently no clinically available colistin synergis. Here we identify artemisinin derivatives, such as dihydroartemisinin (DHA), that produces a synergistic antibacterial effect with colistin against the majority of Gram-negative bacteria (FIC < 0.5) without induced resistance, particularly those carrying the mcr-1 gene. Mechanism analysis reveals the direct engagement of DHA with the active center of MCR-1 to inhibit the activity of MCR-1. Meanwhile, the results from transcriptome and electron microscope analysis show that DHA could also simultaneously affect the flagellar assembly and the energy metabolism of bacteria. Moreover, in the mouse infection models of Gram-negative bacteria, combination therapy shows remarkable treatment benefits, as shown by an improved survival rate, reduced morbidity, alleviated pathological injury and decreased bacterial loading. Due to the generally safe profile of specialized malaria medication administration in humans, artemisinin derivatives are a promising class of multi-target inhibitors on bacterial resistance and virulence that can be used to extend the usage life of colistin and to tackle the inevitability of serious bacterial infection with colistin. The anti-malaria drugs artemisinin derivatives produce a synergistic antibacterial effect with colistin against Gram-negative bacteria by simultaneously inhibiting MCR-1 function and hindering flagella assembly and energy metabolism. [ABSTRACT FROM AUTHOR]

Dehydroabietic acid is a tricyclic diterpenoid resin acid isolated from rosin. Dehydroabietic acid and its derivatives showed lots of medical and agricultural bioactivities, such as anticancer, antibacterial, antiviral, antiulcer, insecticidal, and herbicidal activities. This review summarized the research advances on the structural modification and total synthesis of dehydroabietic acid and its derivatives from 2015 to 2021, and analyzed the biotransformation and structure-activity relationships in order to provide a reference for the development and utilization of dehydroabietic acid and its derivatives as drugs and pesticides. [ABSTRACT FROM AUTHOR]

Chalcone is a naturally derived compound which has well-known for its antimicrobial potency. Different factors reduced the efficiency of drug derivatives effective drugs always remain in demand. In this present work, bioisosteric replacement of carboxyl group is described in 1a–h, 2a–h, 3a–h and 4a–h) via microwave-assisted synthesis with excellent yields (46.76–94.59%). The antimicrobial evaluation against S. aureus depicted excellent inhibition of 1b, 1h and 3a–h with higher inhibition zones (11–18 mm) compared to that of ampicillin (11 mm). The structure-activity relationship was supported by molecular docking studies of 1b and 3h on S. aureus 4-pql protein with the binding affinity of −6.7 and −7.8 kcal/mol respectively. The DFT studies depicted the energy gap (ΔE) values 4.12 eV and 4.48 eV for compounds 1b and 3h, respectively. The presence of electron-withdrawing group (EWG) of fluorine substituent on the pyrazoline network has increased the antimicrobial activity as compared to chalcone derivatives. This study is profitable to medicinal industries in designing new drugs that benefit mankind. [ABSTRACT FROM AUTHOR]

Isotretinoin is a retinoid derivative drug used in acne vulgaris treatment. Sacroiliitis has been reported as an uncommon adverse effect following isotretinoin treatment. We report a 30-yearold male patient who developed sacroiliitis after isotretinoin use. Stopping treatment with isotretinoin resulted in a complete disappearance of inflammatory back pain. A literature search was performed to assess the relevance of this association in everyday clinical practice, and to discuss whether the link between isotretinoin and sacroiliitis is causal or coincidental. [ABSTRACT FROM AUTHOR]

Artemisinin, isolated from the traditional Chinese medicinal plant qīng hāo 青蒿 (Artemisia annua) and its derivatives are used for treatment of malaria. With treatment failures now being recorded for the derivatives and companion drugs used in artemisinin combination therapies new drug combinations are urgently required. The amino-artemisinins artemiside and artemisone display optimal efficacies in vitro against asexual and sexual blood stages of the malaria parasite Plasmodium falciparum and are active against tumour cell lines. In continuing the evolution of combinations of the amino-artemisinins with new drugs, we examine the triterpenoid quinone methide celastrol isolated from the traditional Chinese medicinal plant léi gōng téng 雷公藤 (Tripterygium wilfordii). This compound is redox active, and has attracted considerable attention because of potent biological activities against manifold targets. We report that celastrol displays good IC50 activities ranging from 0.50-0.82 µM against drug-sensitive and resistant asexual blood stage Pf, and 1.16 and 0.28 µM respectively against immature and late stage Pf NF54 gametocytes. The combinations of celastrol with each of artemisone and methylene blue against asexual blood stage Pf are additive. Given that celastrol displays promising antitumour properties, we examined its activities alone and in combinations with amino-artemisinins against human liver HepG2 and other cell lines. IC50 values of the aminoartemisinins and celastrol against HepG2 cancer cells ranged from 0.55-0.94 µM. Whereas the amino-artemisinins displayed notable selectivities (SI > 171) with respect to normal human hepatocytes, in contrast, celastrol displayed no selectivity (SI < 1). The combinations of celastrol with artemiside or artemisone against HepG2 cells are synergistic. Given the promise of celastrol, judiciously designed formulations or structural modifications are recommended for mitigating its toxicity. [ABSTRACT FROM AUTHOR]