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The substantial impact of acyclic nucleoside phosphonates (ANPs) on human medicine encourages the synthesis of new ANP analogues with a potentially differentiated antiviral spectrum. Herein, we demonstrate the functionalization of the 2-position of the (R,S)-3-hydroxy-2-(phosphonomethoxy)propyl side-chain of an inactive ANP with a polar cyano group to generate a thymine analogue with selective inhibition of hepatitis B virus (HBV) replication (SI > 302; EC50 = 0.33 μM), without significant antiretroviral activity. These findings suggest new strategies to synthesize unique ANPs with a targeted antiviral profile. ispartof: RSC MEDICINAL CHEMISTRY vol:12 issue:5 pages:804-808 ispartof: location:England status: published

Taking the previously reported compound BH-7d as the lead, we designed and synthesized a series of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidines, and their anti-HIV activities as well as cytotoxicities were evaluated. Several compounds exhibited moderate anti-HIV (IIIB) potency, among which 2b was the most active one (EC50 = 4.29 μM). Structure-activity relationships derived from the antiretroviral results were analyzed. Additionally, most compounds demonstrated reduced cytotoxicity (CC50 > 200 μM) compared with those of BH-7d and etravirine. Molecular docking study further revealed the binding conformation of 2b in the binding pocket of HIV-1 reverse transcriptase. ispartof: CHEMICAL BIOLOGY & DRUG DESIGN vol:97 issue:1 pages:67-76 ispartof: location:England status: published

The success of metal‐based anticancer therapeutics in the treatment of cancer is best exemplified by cisplatin. Currently used in 32/78 cancer regimens, metal‐based drugs have a clear role in cancer therapy. Despite this, metal‐based anticancer therapeutics are not without drawbacks, with issues such as toxic side effects and the development of resistance mechanisms. This has led to investigations of other metal‐based drug candidates such as auranofin, a gold‐based drug candidate as well as ruthenium‐based candidates, NAMI‐A, NKP‐1339 and TLD‐1433. All are currently undergoing clinical trials. Another class of complexes under study are rhenium‐based; such complexes have undergone extensive in vitro testing but only nine have been reported to display antitumour in vivo activity, which is a necessary step before entering clinical trials. This review will document, chronologically, the rhenium‐based drug candidates that have undergone in vivo testing and the outlook for such complexes., Beyond cisplatin: The use of animal models, otherwise known as in vivo testing, is a crucial step in drug development. To date there have only been nine reported cases of rhenium‐based complexes undergoing in vivo testing. This concept article explores the history of these complexes.

Triple-negative breast cancer (TNBC) is a cancer subtype critically dependent upon excessive activation of Wnt pathway. The anti-mycobacterial drug clofazimine is an efficient inhibitor of canonical Wnt signaling in TNBC, reducing tumor cell proliferation in vitro and in animal models. These properties make clofazimine a candidate to become first targeted therapy against TNBC. In this work, we optimized the clofazimine structure to enhance its water solubility and potency as a Wnt inhibitor. After extensive structure-activity relationships investigations, the riminophenazine 5-(4-(chlorophenyl)-3-((2-(piperazin-1-yl)ethyl)imino)-N-(pyridin-3-yl)-3,5-dihydrophenazin-2-amine (MU17) was identified as the new lead compound for the riminophenazine-based targeted therapy against TNBC and Wnt-dependent cancers. Compared to clofazimine, the water-soluble MU17 displayed a 7-fold improved potency against Wnt signaling in TNBC cells resulting in on-target suppression of tumor growth in a patient-derived mouse model of TNBC. Moreover, allowing the administration of reduced yet effective dosages, MU17 displayed no adverse effects, most notably no clofazimine-related skin coloration. ispartof: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol:222 ispartof: location:France status: published

International audience; Theranostics involves finding the biomarkers of a disease, fighting them through site specific drug delivery and following them for prognosis of the disease. Microneedle array technology has been used for drug delivery and extended for continuous monitoring of analytes present in the skin compartment. We envisage the use of microneedle arrays for future theranostic applications. The potential of combining microneedle array-based drug delivery and diagnostics as part of closed-loop control system for the management of diseases and delivery of precision drugs in individual patients is reported in this paper.

[Image: see text] Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a β-lactamase-cleavable motif. The prodrug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.

Oxidized low-density lipoproteins play an important role in tissue pathology. In this study, we report a sensitive novel enzyme-linked immunosorbent assay for the detection of malondialdehyde-modified low-density lipoprotein (MDA-LDL), a key component of oxidized LDL. The assay is capable of measuring a variable presence of MDA-LDL within human plasma and serum. We demonstrate the robust nature of the assay on samples stored for over 20 months, as well as high inter-operator reproducibility (r = 0.74, p &lt, 0.0001). The assay was capable of detecting dynamic changes in patient blood samples after coronary artery bypass graft surgery, indicating synthesis or release of MDA-LDL with the oxidative stress of surgery, followed by homeostatic clearance. This robust, sensitive and specific assay for circulating MDA-LDL will serve as a valuable translational tool for the improved detection of oxidative forms of LDL in response to a range of physiological or pathological stimuli, with potential clinical applicability.

A series of novel heteroaromatic-difluoro-biphenyl-diarylpyrimidines were designed as non-nucleoside anti-HIV inhibitors targeting reverse transcriptase by a fragment-based replacement strategy with the purpose of improving the druggability. Hopping five- or six-membered heterocycle groups on the biphenyl moiety as bioisosterism for intrinsically cyanophenyl gave 23 derivatives. All of these compounds possessed excellent HIV-1 inhibitory activity in the nanomolar range. Among them, 12g with a 4-pyridine group displayed excellent inhibitory activity toward WT and mutant HIV virus possessing significant selectivity. Moreover, this compound exhibited a decent improvement in druggability than etravirine and rilpivirine: (1) The hydrochloric acid salt of 12g exhibited significantly improved water solubility in different pH conditions. (2) 12g did not show apparent CYP enzymatic inhibitory activity or acute toxicity. (3) Excellent oral bioavailability was also revealed (F = 126%, rats) in 12g. Collectively, these novel heteroaromatic-biphenyl-DAPYs represent promising drug candidates for HIV clinical therapy. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:64 issue:14 pages:10297-10311 ispartof: location:United States status: published

To further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), a new series of diarylpyrimidines (DAPYs) were designed and synthesized as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs). The target compounds were evaluated for anti-HIV potency in MT-4 cells. Most of the synthesized DAPYs exhibited moderate to excellent activity against the HIV-1 wild-type (WT) strain with EC50 values ranging from 16 nM to 0.722 µM. Interestingly, few compounds displayed remarkable activity in inhibiting K103N mutant virus with EC50 values ranging from 39 nM to 1.708 µM. Notably, FS2 (EC50(IIIB) = 16 nM, EC50(K103N) = 39 nM, SI = 294) was identified as the most significant compound, which was considerably more potent than nevirapine, lamivudine, and comparable to zidovudine. Additionally, the HIV-1 RT inhibition assay confirmed their binding target. Preliminary structure-activity relationships (SARs) and molecular modeling studies were also performed, providing significant suggestions for further optimization. ispartof: BIOORGANIC & MEDICINAL CHEMISTRY vol:42 ispartof: location:England status: published

Urease plays a significant role in the pathogenesis of urolithiasis pyelonephritis, urinary catheter encrustation, hepatic coma, hepatic encephalopathy, and peptic acid duodenal ulcers. Salvinia molesta was explored to identify new bioactive compounds with particular emphasis on urease inhibitors. The aqueous methanol extract was fractionated using solvents of increasing polarity. A series of column chromatography and later HPLC were performed on butanol extract. The structures of the resulting pure compounds were resolved using NMR (1D and 2D), infrared, and mass spectroscopy. The novel isolate was evaluated for antioxidant activity (using DPPH, superoxide anion radical scavenging, oxidative burst, and Fe+2 chelation assays), anti-glycation behavior, anticancer activity, carbonic anhydrase inhibition, phosphodiesterase inhibition, and urease inhibition. One new glucopyranose derivative 6'-O-(3,4-dihydroxybenzoyl)-4'-O-(4-hydroxybenzoyl)-α/β-D-glucopyranoside (1) and four known glycosides were identified. Glycoside 1 demonstrated promising antioxidant potential with IC50 values of 48.2 ± 0.3, 60.3 ± 0.6, and 42.1 ± 1.8 μM against DPPH, superoxide radical, and oxidative burst, respectively. Its IC50 in the Jack bean urease inhibition assay was 99.1 ± 0.8 μM. The mechanism-based kinetic studies presented that compound 1 is a mixed-type inhibitor of urease with a Ki value of 91.8 ± 0.1 μM. Finally, molecular dynamic simulations exploring the binding mode of compound 1 with urease provided quantitative agreement between estimated binding free energies and the experimental results. The studies corroborate the use of compound 1 as a lead for QSAR studies as an antioxidant and urease inhibitor. Moreover, it needs to be further evaluated through the animal model, that is, in vivo or tissue culture-based ex-vivo studies, to establish their therapeutic potential against oxidative stress phosphodiesterase-II and urease-induced pathologies. ispartof: DRUG DEVELOPMENT RESEARCH vol:82 issue:8 pages:1169-1181 ispartof: location:United States status: published

Two decades of research have proven the relevance of ion channel expression for tumor progression in virtually every indication, and it has become clear that inhibition of specific ion channels will eventually become part of the oncology therapeutic arsenal. However, ion channels play relevant roles in all aspects of physiology, and specificity for the tumor tissue remains a challenge to avoid undesired effects. Eag1 (KV 10.1) is a voltage-gated potassium channel whose expression is very restricted in healthy tissues outside of the brain, while it is overexpressed in 70% of human tumors. Inhibition of Eag1 reduces tumor growth, but the search for potent inhibitors for tumor therapy suffers from the structural similarities with the cardiac HERG channel, a major off-target. Existing inhibitors show low specificity between the two channels, and screenings for Eag1 binders are prone to enrichment in compounds that also bind HERG. Rational drug design requires knowledge of the structure of the target and the understanding of structure-function relationships. Recent studies have shown subtle structural differences between Eag1 and HERG channels with profound functional impact. Thus, although both targets' structure is likely too similar to identify leads that exclusively bind to one of the channels, the structural information combined with the new knowledge of the functional relevance of particular residues or areas suggests the possibility of selective targeting of Eag1 in cancer therapies. Further development of selective Eag1 inhibitors can lead to first-in-class compounds for the treatment of different cancers. ispartof: MEDICINAL RESEARCH REVIEWS vol:42 issue:1 pages:183-226 ispartof: location:United States status: published

The cytokine interleukin-7 (IL-7) and its receptor are critical for lymphoid cell development. The loss of IL-7 signaling causes severe combined immunodeficiency, whereas gain-of-function alterations in the pathway contribute to malignant transformation of lymphocytes. Binding of IL-7 to the IL-7 receptor results in the activation of the JAK-STAT, PI3K-AKT and Ras-MAPK pathways, each contributing to survival, cell cycle progression, proliferation and differentiation. Here, we discuss the role of deregulated IL-7 signaling in lymphoid malignancies of B- and T-cell origin. Especially in T-cell leukemia, more specifically in T-cell acute lymphoblastic leukemia and T-cell prolymphocytic leukemia, a high frequency of mutations in components of the IL-7 signaling pathway are found, including alterations in IL7R, IL2RG, JAK1, JAK3, STAT5B, PTPN2, PTPRC and DNM2 genes. ispartof: PHARMACEUTICALS vol:14 issue:5 ispartof: location:Switzerland status: published

This study aimed to compare drug costs and healthcare costs of a 1 year adjuvant course with intravenous biosimilar trastuzumab vs. subcutaneous reference trastuzumab in HER2-positive breast cancer from the Belgian hospital perspective. Our simulation is based on the methodology used by Tjalma and colleagues, and considered costs of drugs, healthcare professional time and consumables. We calculated intravenous drug costs for different body weights, and computed drug costs and healthcare costs to treat 100 patients with either trastuzumab formulation, assuming a binomial body weight distribution in this sample. Scenarios were run to account for drug discounts and intravenous vial sharing. Drug costs amounted to €1,431,282 with intravenous biosimilar trastuzumab and €1,522,809 with subcutaneous reference trastuzumab for a sample of 100 patients in the base case analysis. When healthcare professional time and consumables were also considered, healthcare costs with intravenous biosimilar trastuzumab were similar to those with subcutaneous reference trastuzumab. Differences in healthcare costs between intravenous biosimilar trastuzumab and subcutaneous reference trastuzumab depended on the level of discounts on these formulations and on intravenous vial sharing. Our case study demonstrates that comparing costs of intravenous vs. subcutaneous formulations is complex and multifactorial, and entails more than a simple cost comparison of products. ispartof: PHARMACEUTICALS vol:14 issue:5 ispartof: location:Switzerland status: published

ETHNOPHARMACOLOGICAL RELEVANCE: Tetradenia riparia (commonly known as ginger bush) is frequently used in traditional African medicine to treat foodborne infections including diarrhoea, gastroenteritis, and stomach ache. AIM OF THE STUDY: The present study aims to identify in Tetradenia riparia the compounds active against foodborne pathogens. MATERIALS AND METHODS: Dried Tetradenia riparia leaf powder was consecutively extracted with hexane, ethyl acetate, methanol and water. The hexane extract was counter-extracted with methanol:water (9:1), and after evaporation of the methanol, this phase was extracted with dichloromethane. The water extract was counter-extracted with butanol. All these fractions were tested against a panel of foodborne bacterial pathogens. A bioassay-guided purification was performed to isolate antimicrobial compounds using Staphylococcus aureus as a target organism. Further, antibiofilm activity was evaluated on S. aureus USA 300. RESULTS: The dichloromethane fraction and ethyl acetate extract were the most potent, and therefore subjected to silica gel chromatography. From the dichloromethane fraction, one active compound was crystalized and identified using NMR as 8(14),15-sandaracopimaradiene-7alpha, 18-diol (compound 1). Two active compounds were isolated from the ethyl acetate extract: deacetylumuravumbolide (compound 2) and umuravumbolide (compound 3). Using a microdilution method, their antimicrobial activity was tested against eight foodborne bacterial pathogens: Shigella sonnei, S. flexneri, Salmonella enterica subsp. enterica, Escherichia coli, Micrococcus luteus, S. aureus, Enterococcus faecalis, and Listeria innocua. Compound 1 had the strongest activity (IC50 ranging from 11.2 to 212.5 μg/mL), and compounds 2 and 3 showed moderate activity (IC50 from 212.9 to 637.7 μg/mL and from 176.1 to 521.4 μg/mL, respectively). Interestingly, 8(14),15-sandaracopimaradiene-7alpha, 18-diol is bactericidal, and also showed good antibiofilm activity with BIC50 (8.8 ± 1.5 μg/mL) slightly lower than for planktonic cells (11.4 ± 2.8 μg/mL). CONCLUSIONS: These results support the traditional use of this plant to conserve foodstuffs and to treat gastrointestinal ailments, and open perspectives for its use in the prevention and treatment of foodborne diseases. ispartof: JOURNAL OF ETHNOPHARMACOLOGY vol:273 ispartof: location:Ireland status: published

Nucleoside analogue reverse transcriptase inhibitors (NRTI) and nucleoside analogue monophosphate prodrugs are used in combination antiretroviral therapy (cART). The design of antivirally active nucleoside triphosphate prodrugs is a recent and an important advancement in the field of nucleoside analogue drug development. Here, we report on TriPPPro‐derivatives of nucleoside analogue triphosphates (NTPs) that comprised two different acyloxybenzyl‐masks at the γ‐phosphate of the NTP aiming to achieve the metabolic bypass. Thus, γ‐non‐symmetrically dimasked TriPPPro‐compounds (γ‐(AB,ab)‐d4TTPs) were synthesized and they proved to be active against HIV‐1 and HIV‐2 in cultures of infected wild‐type human CD4+ T‐lymphocyte (CEM/0) cells and more importantly also in thymidine kinase‐deficient CD4+ T‐cells (CEM/TK‐). From hydrolysis studies both in phosphate buffer (PB, pH 7.3) and CEM cell extracts, there was surprisingly no differentiation in the cleavage of the two acyloxybenzyl prodrug‐masks. However, if within one of the two acyloxybenzyl groups a short PEG‐type methoxytriglycol group was introduced, the “standard” acyloxybenzyl‐mask was cleaved with high preference., Masked and ready: Lipophilic nucleoside triphosphate prodrugs bearing two different bioreversible masking groups attached to the γ‐position of the triphosphate moiety were studied. The aim to use two different masking groups was to enhance the selectivity of their removal during the cleavage process in order to deliver nucleoside triphosphates intracellularly. The compounds proved to be active against HIV even in cells lacking a phosphorylating enzyme.

Several studies have reported neuroprotective effects by natural products. A wide range of natural compounds have been investigated, and some of these may play a beneficial role in Alzheimer's disease (AD) progression. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been implicated in AD. In particular, MMP-2 and MMP-9 are able to trigger several neuroinflammatory and neurodegenerative pathways. In this review, we summarize and discuss existing literature on natural marine and terrestrial compounds, as well as their ability to modulate MMP-2 and MMP-9, and we evaluate their potential as therapeutic compounds for neurodegenerative and neuroinflammatory diseases, with a focus on Alzheimer's disease. ispartof: PHARMACEUTICALS vol:14 issue:2 ispartof: location:Switzerland status: published

We used classical linear and microwave-assisted synthesis methods to prepare novel N-substituted, benzimidazole-derived acrylonitriles with antiproliferative activity against several cancer cells in vitro. The most potent systems showed pronounced activity against all tested hematological cancer cell lines, with favorable selectivity towards normal cells. The selection of lead compounds was also tested in vitro for tubulin polymerization inhibition as a possible mechanism of biological action. A combination of docking and molecular dynamics simulations confirmed the suitability of the employed organic skeleton for the design of antitumor drugs and demonstrated that their biological activity relies on binding to the colchicine binding site in tubulin. In addition, it also underlined that higher tubulin affinities are linked with (i) bulkier alkyl and aryl moieties on the benzimidazole nitrogen and (ii) electron-donating substituents on the phenyl group that allow deeper entrance into the hydrophobic pocket within the tubulin's β-subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues. ispartof: PHARMACEUTICALS vol:14 issue:10 ispartof: location:Switzerland status: published

Aims: An abundance of epidemiological evidence demonstrates that elevated lipoprotein(a) (Lp(a)) represents a significant contributing risk factor towards the development of cardiovascular disease. In particular, raised Lp(a) may play a mechanistic role in patients with refractory angina. Studies have also shown a correlation between oxidised LDL (oxLDL) levels and atherosclerotic burden as well as rates of cardiovascular events. Antibodies against oxLDL (anti-oxLDL) are involved in the removal of oxLDL. Lipoprotein apheresis (LA), which removes lipoproteins using extra-corporeal processes, is an established means of reducing Lp(a), and thereby reduces cardiovascular events. The aim of this study was to investigate the effect of LA on oxLDL and anti-oxLDL levels amongst those with refractory angina in the context of raised Lp(a). Methods: We performed a sub-study within a randomised controlled crossover trial involving 20 patients with refractory angina and raised Lp(a) &gt, 500 mg/L, comparing the effect of three months of blinded weekly LA or sham, followed by crossover to the opposite study arm. We utilized enzyme-linked immunosorbent assays (ELISA) to quantify oxLDL and IgG/ IgM anti-oxLDL antibody levels at baseline and following three months of active LA or sham sessions. Results: Following three months of LA, there was a 30% reduction in oxLDL from 0.37 &plusmn, 0.06 to 0.26 &plusmn, 0.04 with a mean drop of &minus, 0.11 units (U) (95% CI &minus, 0.13, &minus, 0.09) compared to no significant change with sham therapy (p &lt, 0.0001 between treatment arms). LA also led to a 22% reduction in levels of IgG and IgM anti-oxLDL, again with no significant change demonstrated during sham (p = 0.0036 and p = 0.012, respectively, between treatment arms). Conclusion: Amongst patients with refractory angina in the context of elevated Lp(a), LA significantly lowers levels of oxLDL and anti-oxLDL antibodies, representing potential mechanisms by which LA yields symptomatic and prognostic benefits in this patient cohort.

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © 2021 American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.0c00382. Despite the recent advances in cancer therapeutics, highly aggressive cancer forms, such as glioblastoma (GBM), still have very low survival rates. The intracellular scaffold protein syntenin, comprising two postsynaptic density protein-95/discs-large/zona occludens-1 (PDZ) domains, has emerged as a novel therapeutic target in highly malignant phenotypes including GBM. Here, we report the development of a novel, highly potent, and metabolically stable peptide inhibitor of syntenin, KSL-128114, which binds the PDZ1 domain of syntenin with nanomolar affinity. KSL-128114 is resistant toward degradation in human plasma and mouse hepatic microsomes and displays a global PDZ domain selectivity for syntenin. An X-ray crystal structure reveals that KSL-128114 interacts with syntenin PDZ1 in an extended noncanonical binding mode. Treatment with KSL-128114 shows an inhibitory effect on primary GBM cell viability and significantly extends survival time in a patient-derived xenograft mouse model. Thus, KSL-128114 is a novel promising candidate with therapeutic potential for highly aggressive tumors, such as GBM.

In this study, synthesis and characterization of naphthalimide derivatives containing both amide and urea groups were performed and their antioxidant activities were determined. 4-R-1 8-naphthalic anhydride (R = -H, -NO2 or –NH2) with different functional groups has been chosen as the precursor and reacted with 5,6-diamino-1H-benzo[d]imidazol-2(3H)-one to synthesize the targeted naphthalimide derivatives. ESI-MS and 1H-NMR techniques have been used to characterize the molecules. Antioxidant activities of compounds have been determined by DPPH and peroxide radical scavenging methods.

New mononuclear complexes [Mn(NO3)(sac)(H2O)(bzimpy)]center dot 2DMF (Mn), [Fe(sac)(2)(H2O)(bzimpy)]center dot 2H(2)O (Fe), [Co(bzimpy)(2)](sac)(2)center dot 2H(2)O (Co), [Ni(bzimpy)(2)](sac)(2)center dot H2O center dot i-PrOH (Ni) and [Cu(sac)(2)(bzimpy)]center dot 3DMF (Cu) (sac = saccharinate and bzimpy = 2,6-bis(2-benzimidazolyl)pyridine) were synthesized and structurally characterized by elemental analysis, UV-Vis, IR, ESI-MS and X-ray diffraction. The anticancer activity of the metal complexes against A549 (lung), MCF-7 (breast), HT29 (colon) cancer cells and MCF10A (normal human breast epithelial) cells was tested and compared with those of cisplatin and bzimpy. The complexes displayed potent cytotoxic activity especially in MCF-7 and A549 cell lines, but they were practically inactive against the normal cells. Mechanistic studies with Mn and Cu complexes on A549 cells indicated that the complexes induced G0/G1 arrest. Both complexes increased intracellular ROS (reactive oxygen species) levels and successfully caused both mitochondrial dysfunction and doublestrand DNA breaks. The up-regulated Bax and down-regulated Bcl-2 expression levels, caspase-3/7 activation and reduced Fas expression indicated that Mn and Cu induced ROS-dependent mitochondria-mediated intrinsic apoptosis in A549 cells. (C) 2020 Elsevier Masson SAS. All rights reserved.

Hospital-acquired bacterial infections are a significant burden on healthcare systems worldwide causing an increased duration of hospital stays and prolonged patient suffering. We show that polyurethane containing crystal violet (CV) and 3–4 nm zinc oxide nanoparticles (ZnO NPs) possesses excellent bactericidal activity against hospital-acquired pathogens including multidrug resistant Escherichia coli (E. coli), Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), and even highly resistant endospores of Clostridioides (Clostridium) difficile. Importantly, we used clinical isolates of bacterial strains, a protocol to mimic the environmental conditions of a real exposure in the healthcare setting, and low light intensity equivalent to that encountered in UK hospitals (∼500 lux). Our data shows that ZnO NPs enhance the photobactericidal activity of CV under low intensity light even with short exposure times, and we show that this involves both Type I and Type II photochemical pathways. Interestingly, polyurethane containing ZnO NPs alone showed significant bactericidal activity in the dark against one strain of E. coli, indicating that the NPs possess both light-activated synergistic activity with CV and inherent bactericidal activity that is independent of light. These new antibacterial polymers are potentially useful in healthcare facilties to reduce the transmission of pathogens between people and the environment.

The HIV-1 CA protein has gained remarkable attention as a promising therapeutic target for the development of new antivirals, due to its pivotal roles in HIV-1 replication (structural and regulatory). Herein, we report the design and synthesis of three series of benzenesulfonamide-containing phenylalanine derivatives obtained by further structural modifications of PF-74 to aid in the discovery of more potent and drug-like HIV-1 CA inhibitors. Structure-activity relationship studies of these compounds led to the identification of new phenylalanine derivatives with a piperazinone moiety, represented by compound 11l, which exhibited anti-HIV-1NL4-3 activity 5.78-fold better than PF-74. Interestingly, 11l also showed anti-HIV-2ROD activity (EC50 = 31 nM), with almost 120 times increased potency over PF-74. However, due to the higher significance of HIV-1 as compared to HIV-2 for the human population, this manuscript focuses on the mechanism of action of our compounds in the context of HIV-1. SPR studies on representative compounds confirmed CA as the binding target. The action stage determination assay demonstrated that these inhibitors exhibited antiviral activities with a dual-stage inhibition profile. The early-stage inhibitory activity of compound 11l was 6.25 times more potent as compared to PF-74 but appeared to work via the accelerating capsid core assembly rather than stabilization. However, the mechanism by which they exert their antiviral activity in the late stage appears to be the same as PF-74 with less infectious HIV-1 virions produced in their presence, as judged p24 content studies. MD simulations provided the key rationale for the promising antiviral potency of 11l. Additionally, 11l exhibited a modest increase in HLM and human plasma metabolic stabilities as compared to PF-74, as well as a moderately improved pharmacokinetic profile, favorable oral bioavailability, and no acute toxicity. These studies provide insights and serve as a starting point for subsequent medicinal chemistry efforts in optimizing these promising HIV inhibitors. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:63 issue:9 pages:4790-4810 ispartof: location:United States status: published

Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 μL/min/mg (human) and 33.2 μL/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 μL/min/mg; rat, 33.2 μL/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions. ispartof: ACS INFECTIOUS DISEASES vol:6 issue:5 pages:787-801 ispartof: location:United States status: published

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent potent anti-HIV agents targeting HIV-1 reverse transcriptase (RT), a crucial enzyme for the viral life cycle. We have previously identified a series of NNRTIs bearing a 2,3-diaryl-1,3-thiazolidin-4-one core and some compounds proved to be effective in inhibiting HIV-1 replication at micromolar concentration. As a continuation in this research work we report the design, the synthesis and the structure-activity relationship studies of a further series of 3-(1,3,4-thiadiazol-2-yl)thiazolidin-4-one derivatives containing an arylthioacetamide group as pharmacophoric structural requirement for binding to the RT catalytic area. The new compounds proved to be effective to inhibit RT activity at micromolar concentrations. Finally, docking studies were carried out in order to rationalize the biological results of the new synthesized inhibitors. ispartof: Bioorganic & Medicinal Chemistry vol:28 issue:8 ispartof: location:England status: published

Heteroarene-fused anthraquinone derivatives represent a class of perspective anticancer drug candidates capable of targeting multiple vital processes including drug resistance. Taking advantage of previously demonstrated potential of amide derivatives of heteroarene-fused anthraquinones, we herein dissected the role of the heterocyclic core in antitumor properties. A new series of naphtho[2,3-f]indole-3- and anthra[2,3-b]thiophene-3-carboxamides was synthesized via coupling the respective acids with cyclic diamines. New compounds demonstrated a submicromolar antiproliferative potency close to doxorubicin (Dox) against five tumor cell lines of various tissue origin. In contrast to Dox, the new compounds were similarly cytotoxic for HCT116 colon carcinoma cells (wild type p53) and their isogenic p53 knockout counterparts. Modification of the heterocyclic core changed the targeting properties: the best-in-series naphtho[2,3-f]indole-3-carboxamide 8 formed more affine complexes with DNA duplex than furan and thiophene analogs, a property that can be translated into a stronger inhibition of topoisomerase 1 mediated DNA unwinding. At tolerable doses the water soluble derivative 8 significantly inhibited tumor growth (up to 79%) and increased the lifespan (153%) of mice bearing P388 lymphoma transplants. Together with better solubility for parenteral administration and well tolerance by animals of the indole derivative 8 indicates prospects for further search of new antitumor drug candidates among the heteroarene-fused anthraquinones. ispartof: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol:199 ispartof: location:France status: published

2019 has been an excellent year in terms of peptides and oligonucleotides (TIDES) approved by the FDA. Despite the drop in the number of total drugs approved by the FDA in 2019 in comparison with 2018 (48 vs. 59), the total number of TIDES authorized increased (seven vs. three). Year after year, TIDES are increasingly present in therapy, as imaging agents, theragnostic and constituent moieties of other complex drugs, such as antibody drug conjugates. This means a consolidation of these kinds of drugs in the pharmaceutical arena, paving the way in the coming years for the approval of others for diverse medical indications. Here the TIDES approved in 2019 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.

Desymmetrisation of robenidine (1: N ',2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 mu g mL(-1). Five analogues were found to be equipotent or more potent than the lead 1. Introduction of an indole moiety resulted in the most active robenidine analogue against methicillin-resistant S. aureus (MRSA), with a MIC of 1.0 mu g mL(-1). Imine C=NH isosteres (C=O/C=S) were inactive. Monomeric analogues were 16-64 mu g mL(-1) active against MRSA and VRE. An analogue that lacks the terminal hydrazide NH moiety showed modest Gram-negative activity at 64 mu g mL(-1). A 4-tert-butyl analogue was shown to be active against both Gram-positive and -negative strains at 16-64 mu g mL(-1). In general, additional modifications with aromatic moieties was poorly tolerated, except with concomitant introduction of an imine C-alkyl group. The activity of these analogues against MRSA and VRE ranged from 8 mu g mL(-1) to inactive (MIC>128 mu g mL(-1)) with the naphthyl and indole analogues. Gram-negative activity was most promising with two compounds at 16 mu g mL(-1) against E. coli. Against P. aeruginosa, the highest activity observed was with MIC values of 32 mu g mL(-1) with another two analogues. Combined, these findings support the further development of the (E)-2-benzylidenehydrazine-1-carboximidamide scaffold as a promising scaffold for the development of antibiotics against Gram-positive and Gram-negative strains. Refereed/Peer-reviewed

Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.

Social and demographic changes across the world over the past 50 years have resulted in significant outbreaks of arboviruses such as dengue virus (DENV) and Zika virus (ZIKV). Despite the increased threat of infection, no approved drugs or fully protective vaccines are available to counteract the spread of DENV and ZIKV. The development of "broad-spectrum" antivirals (BSAs) that target common components of multiple viruses can be a more effective strategy to limit the rapid emergence of viral pathogens than the classic "one-bug/one-drug" approach. Starting from previously identified multitarget DENV inhibitors, herein we report the identification of novel 2,6-diaminopurine derivatives that are able to block the replication of both Zika virus and all serotypes of dengue virus (DENV 1-4) in infected cells. ispartof: CHEMMEDCHEM vol:13 issue:14 pages:1371-1376 ispartof: location:Germany status: published

Membrane proteins allow effective communication between cells and organelles and their external environments. Maintaining membrane protein stability in a non‐native environment is the major bottleneck to their structural study. Detergents are widely used to extract membrane proteins from the membrane and to keep the extracted protein in a stable state for downstream characterisation. In this study, three sets of steroid‐based amphiphiles—glyco‐diosgenin analogues (GDNs) and steroid‐based pentasaccharides either lacking a linker (SPSs) or containing a linker (SPS‐Ls)—have been developed as new chemical tools for membrane protein research. These detergents were tested with three membrane proteins in order to characterise their ability to extract membrane proteins from the membrane and to stabilise membrane proteins long‐term. Some of the detergents, particularly the SPS‐Ls, displayed favourable behaviour with the tested membrane proteins. This result indicates the potential utility of these detergents as chemical tools for membrane protein structural study and a critical role of the simple alkyl spacer in determining detergent efficacy.

Further clinical development of PF74, a lead compound targeting HIV-1 capsid, is impeded by low antiviral activity and inferior metabolic stability. By modifying the benzene (region I) and indole of PF74, we identified two potent compounds (7m and 7u) with significantly improved metabolic stability. Compared to PF74, 7u displayed greater metabolic stability in human liver microsomes (HLMs) with half-life (t1/2) 109-fold that of PF74. Moreover, mechanism of action (MOA) studies demonstrated that 7m and 7u effectively mirrored the MOA of compounds that interact within the PF74 interprotomer pocket, showing direct and robust interactions with recombinant CA, and 7u displaying antiviral effects in both the early and late stages of HIV-1 replication. Furthermore, MD simulation corroborated that 7u was bound to the PF74 binding site, and the results of the online molinspiration software predicted that 7m and 7u had desirable physicochemical properties. Unexpectedly, this series of compounds exhibited better antiviral activity than PF74 against HIV-2, represented by compound 7m whose anti-HIV-2 activity was almost 5 times increased potency over PF74. Therefore, we have rationally redesigned the PF74 chemotype to inhibitors with novel structures and enhanced metabolic stability in this study. We hope that these new compounds can serve as a blueprint for developing a new generation of HIV treatment regimens. ispartof: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol:227 ispartof: location:France status: published

Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I2-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile. Moreover, LSL60101 induced hypothermia in mice while decreased pro-apoptotic FADD protein in the hippocampus. In vivo studies in the familial Alzheimer's disease 5xFAD murine model with the representative compound, revealed significant decreases in the protein expression levels of antioxidant enzymes superoxide dismutase and glutathione peroxidase in hippocampus. Overall, LSL60101 plays a neuroprotective role by reducing apoptosis and modulating oxidative stress., This work was supported by Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2019-107991RB-I00, PID2019-106285RB), the Basque Government (IT1211/19) and Generalitat de Catalunya (GC) (2017SGR106). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434) under agreement CI18-00002. This activity has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union's Horizon 2020 research and innovation programme. C.G.-F, F.V., C.E., S.R.-A., A.B., and M.P. Financial support was provided for F.V. (University of Barcelona, APIF_2017), S.R.-A. (Generalitat de Catalunya, 2018FI_B_00227), A.B. (Institute of Biomedicine UB_2018), J.A.G.-S. is a member emeritus of the Institut d’Estudis Catalans (Barcelona, Catalonia). E.H.-H. is supported by a predoctoral scholarship (FPI/2102/2018; Consejería de Innovación, Investigación y Turismo del Gobierno de las Islas Baleares y del Fondo Social Europeo). M.R., T.D., and K.N. kindly acknowledge the project funded by the Ministry of Science and Technological Development of the Republic of Serbia, Contract No. 451-03-68/2020-14/200161, and HORISON 2020-COST-Action CA18133 ERNEST: European Research Network on Signal Transduction. E. M. acknowledges funding to Severo Ochoa: CEX2019-917S. M.I.L, A.L.M. and J.B. gratefully acknowledge support from Xunta de Galicia (ED431C 2018/21 and ED431G 2019/02) and European Regional Development Fund (ERDF)., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).

Metal-based chemotherapeutics such as cisplatin are widely used treatment of lung cancer which is the major cause of cancer-related mortality worldwide. Recent studies demonstrated that novel metal-based compounds have strong cytotoxic activity in a similar way as cisplatin. Therefore, metal-based compounds have been synthesized and investigated in order to determine their cytotoxic activities. It has been also reported curcumin, which has been derived from turmeric plant, has powerful cytotoxic effect on various cancer cell lines. In the light of these data, it has been investigated the cytotoxic effects of combination of curcumin (0.78-100 mu M) and palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine [Pd(II) complex] (0.39-50 mu M) against non small lung cancer cell lines, A549 and H1299. It has been found that combination of Pd(II) complex and curcumin enhanced the cytotoxic activity and apoptotic cell death at 48 h, compared to single use of each agent, only in H1299 cell line (combination index

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:63 issue:9 pages:4562-4578 ispartof: location:United States status: published

The recent outbreaks of Zika virus (ZIKV) infection worldwide make the discovery of novel antivirals against flaviviruses a research priority. This work describes the identification of novel inhibitors of ZIKV through a structure‐based virtual screening approach using the ZIKV NS5‐MTase. A novel series of molecules with a carbazoyl‐aryl‐urea structure has been discovered and a library of analogues has been synthesized. The new compounds inhibit ZIKV MTase with IC50 between 23–48 μM. In addition, carbazoyl‐aryl‐ureas also proved to inhibit ZIKV replication activity at micromolar concentration., Novel antivirals targeting ZIKA virus: The recent outbreaks of Zika virus (ZIKV) worldwide make the discovery of novel antivirals a priority. Using a structure‐based virtual screening approach we were able to identify and develop a novel series of carbazoyl‐urea derivatives that are able to inhibit the ZIKV NS5‐MTase as well as ZIKV replication at micromolar concentration.

Human Immunodeficiency Virus (HIV) damages the immune system and leads to the life-threatening acquired immunodeficiency syndrome (AIDS). Despite the advances in the field of antiretroviral treatment, HIV remains a major public health challenge. Nucleosides represent a prominent chemotherapeutic class for treating viruses, however their cellular uptake, kinase-mediated activation and catabolism are limiting factors. Herein, we report the synthesis and in vitro evaluation of stavudine (d4T) ProTides containing polyfluorinated aryl groups against two strains; HIV-1 (IIIB) and HIV-2 (ROD). ProTide 5d containing a meta-substituted pentafluorosulfanyl (3-SF5) aryl group showed superior antiviral activity over the parent d4T and the nonfluorinated analogue 5a. ProTide 5d has low nanomolar antiviral activity; (IC50 = 30 nM, HIV-1) and (IC50 = 36 nM, HIV-2) which is over tenfold more potent than d4T. Interestingly, ProTide 5d showed a significantly high selectivity indices with SI = 1753 (HIV-1) and 1461 (HIV-2) which is more than twice that of the d4T. All ProTides were screened in wild type as well as thymidine kinase deficient (TK-) cells. Enzymatic activation of ProTide 5d using carboxypeptidase Y enzyme and monitored using both 31P and 19F NMR is presented. ispartof: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol:29 issue:24 ispartof: location:England status: published

In the present study, an in vitro-in vivo extrapolation of dissolution integrated to a physiologically based pharmacokinetics modeling approach, considering a product-specific particle size distribution and a self-buffering effect of the drug, is introduced and appears to be a promising translational modeling strategy to support drug product development, manufacturing changes and setting clinically relevant specifications for immediate release formulations containing ibuprofen and other weak acids with similar properties. ispartof: JOURNAL OF PHARMACEUTICAL SCIENCES vol:108 issue:12 pages:3842-3847 ispartof: location:United States status: published

The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of &alpha, conotoxin MilIA, the first conopeptide from the venom of Conus milneedwardsi. The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in Xenopus laevis oocytes. MilIA, which is a member of the &alpha, 3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for &alpha, 9&alpha, 10 nAChRs among the neuronal types.

Previously, we reported the discovery of 3,6-disubstituted isothiazolo[4,3-b]pyridines as potent and selective cyclin G-associated kinase (GAK) inhibitors with promising antiviral activity. In this manuscript, the structure-activity relationship study was expanded to synthesis of isothiazolo[4,3-b]pyridines with modifications of the pyridine moiety. This effort led to the discovery of an isothiazolo[4,3-b]pyridine derivative with a 3,4-dimethoxyphenyl residue at position 5 that displayed low nanomolar GAK binding affinity and antiviral activity against dengue virus. ispartof: BIOORGANIC & MEDICINAL CHEMISTRY vol:28 issue:1 ispartof: location:England status: published

Insulinomas, neuroendocrine tumors arising from pancreatic beta cells, often show overexpression of the glucagon-like peptide-1 receptor. Therefore, imaging with glucagon-like peptide analog exendin-4 can be used for diagnosis and preoperative localization. This review presents an overview of the development and clinical implementation of exendin-based tracers for nuclear imaging, and the potential use of exendin-4 based tracers for optical imaging and therapeutic applications such as peptide receptor radionuclide therapy or targeted photodynamic therapy.Insulinomas are neuroendocrine tumors arising from the pancreatic beta cells. Currently, surgical resection is the therapy of choice, and therefore, preoperative localization of insulinomas is essential. Nearly all insulinomas show overexpression of the glucagon-like peptide-1 receptor (GLP-1R), and therefore, radiolabeled GLP-1 peptide analog exendin-4 can be used for diagnosis and preoperative localization with nuclear imaging. Here, we present an overview of the development and clinical implementation of exendin-4-based tracers for single-photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging of insulinomas, and we address the potential use of this molecule for optical imaging. At last, we discuss the possibilities and pitfalls of the use of exendin-4-based tracers for therapeutic applications such as peptide receptor radionuclide therapy (PRRT) or targeted photodynamic therapy (tPDT), giving a future outlook on the use of exendin-4 in insulinoma theranostics.

Cisplatin is amongst the most potent chemotherapeutic drugs with applications in more than 50% of cancer treatments, but dose-dependent side effects limit its usefulness. Berberis vulgaris L. (B. vulgaris) has a proven role in several therapeutic applications in the traditional medicinal system. High-performance liquid chromatography was used to quantify berberine, a potent alkaloid in the methanolic root extract of B. vulgaris (BvRE). Berberine chloride in BvRE was found to be 10.29% w/w. To assess the prophylactic and curative protective effects of BvRE on cisplatin-induced nephrotoxicity, hepatotoxicity, and hyperlipidemia, in vivo toxicity trials were carried out on 25 healthy male albino Wistar rats (130&ndash, 180 g). Both prophylactic and curative trials included a single dose of cisplatin (4 mg/kg, i.p.) and nine doses of BvRE (500 mg/kg/day, orally). An array of marked toxicity effects appeared in response to cisplatin dosage evident by morphological condition, biochemical analysis of serum (urea, creatinine, total protein, alanine transaminase, aspartate transaminase, total cholesterol, and triglyceride), and organ tissue homogenates (malondialdehyde and catalase). Statistically-significant (p &lt, 0.05) variations were observed in various parameters. Moreover, histological studies of liver and kidney tissues revealed that the protective effect of BvRE effectively minimized and reversed nephrotoxic, hepatotoxic, and hyperlipidemic effects caused by cisplatin in both prophylactic and curative groups with relatively promising ameliorative effects in the prophylactic regimen. The in vitro cell viability effect of cisplatin, BvRE, and their combination was determined on HeLa cells using the tetrazolium (MTT) assay. MTT clearly corroborated that HeLa cells appeared to be less sensitive to cisplatin and berberine individually, while the combination of both at the same concentrations resulted in growth inhibition of HeLa cells in a remarkable synergistic way. The present validated the use of BvRE as a protective agent in combination therapy with cisplatin.

Antimicrobial resistance (AMR) is a serious issue that could have severe consequences if steps are not taken. The nybomycin natural products have the potential to extend the clinical efficacy of the marketed fluoroquinolone class of antibiotics through a ‘reverse antibiotic’ approach. However, only very limited structure–activity relationships are known for these fascinating compounds, in part due to challenges with their synthesis. Here we report a new scalable and robust synthetic route to the nybomycin natural products to aid in the development of this series. Through this synthesis, we report the antibiotic activity of novel analogues of this family confirming the selectivity for fluoroquinolone resistant bacteria and potential future opportunities for further optimisation.

Reactive oxygen species (ROS) regulate plant growth and development. ROS are kept at low levels in cells to prevent oxidative damage, allowing them to be effective signaling molecules upon increased synthesis. In plants and animals, NADPH oxidase/respiratory burst oxidase homolog (RBOH) proteins provide localized ROS bursts to regulate growth, developmental processes, and stress responses. This review details ROS production via RBOH enzymes in the context of plant development and stress responses and defines the locations and tissues in which members of this family function in the model plant Arabidopsis thaliana. To ensure that these ROS signals do not reach damaging levels, plants use an array of antioxidant strategies. In addition to antioxidant machineries similar to those found in animals, plants also have a variety of specialized metabolites that scavenge ROS. These plant specialized metabolites exhibit immense structural diversity and have highly localized accumulation. This makes them important players in plant developmental processes and stress responses that use ROS-dependent signaling mechanisms. This review summarizes the unique properties of plant specialized metabolites, including carotenoids, ascorbate, tocochromanols (vitamin E), and flavonoids, in modulating ROS homeostasis. Flavonols, a subclass of flavonoids with potent antioxidant activity, are induced during stress and development, suggesting that they have a role in maintaining ROS homeostasis. Recent results using genetic approaches have shown how flavonols regulate development and stress responses through their action as antioxidants. ispartof: CHEMICAL RESEARCH IN TOXICOLOGY vol:32 issue:3 pages:370-396 ispartof: location:United States status: published

Introduction Cannflavins are a group of prenylflavonoids derived from Cannabis sativa L.. Cannflavin A (CFL-A), B (CFL-B) and C (CFL-C) have been heralded for their anti-inflammatory properties in pre-clinical evaluations. This scoping review aims to synthesise the evidence base on cannflavins to provide an overview of the current research landscape to inform research strategies to aid clinical translation. Methods A scoping review was conducted of EMBASE, MEDLINE, Pubmed, CENTRAL and Google Scholar databases up to 26th February 2020. All studies describing original research on cannflavins and their isomers were included for review. Results 26 full text articles were included. CFL-A and CFL-B demonstrated potent anti-inflammatory activity via inhibition of 12-o-tetradecanoylphorbol 13-acetate induced PGE2 release (CFL-A half maximal inhibitory concentration (IC50): 0.7 μM; CFL-B IC50: 0.7 μM) and microsomal prostaglandin E synthase-1 (CFL-A IC50: 1.8 μM; CFL-B IC50: 3.7 μM). Outcomes were also described in preclinical models of anti-oxidation (CFL-A), anti-parasitic activity (CFL-A, CFL-C), neuroprotection (CFL-A) and cancer (Isocannflavin B, a CFL-B isomer). In-silico screening identified that CFL-A has binding affinity with viral proteins that warrant further investigation. Conclusions Cannflavins demonstrate a number of promising therapeutic properties, most notably as an anti-inflammatory agent. Low yields of extraction however have previously limited research to small pre-clinical investigations. Identification of cannflavin-rich chemovars, novel extraction techniques and recent identification of a biosynthetic pathway will hopefully allow research to be scaled appropriately. In order to fully evaluate the therapeutic properties of cannflavins focused research now needs to be embedded within institutions with a track-record of clinical translation.

There is a high need for the development of new and improved antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening of MNPs. To this end, the embryonic zebrafish photomotor response assay and the larval zebrafish pentylenetetrazole (PTZ) model were used to screen MNP extracts for neuroactivity and antiseizure activity, respectively. Here we report the identification of the two known isoquinoline alkaloids TMC-120A and TMC-120B as novel antiseizure compounds, which were isolated by bioactivity-guided purification from the marine-derived fungus Aspergillus insuetus. TMC-120A and TMC-120B were observed to significantly lower PTZ-induced seizures and epileptiform brain activity in the larval zebrafish PTZ seizure model. In addition, their structural analogues TMC-120C, penicisochroman G, and ustusorane B were isolated and also significantly lowered PTZ-induced seizures. Finally, TMC-120A and TMC-120B were investigated in a mouse model of drug-resistant focal seizures. Compound treatment significantly shortened the seizure duration, thereby confirming their antiseizure activity. These data underscore the possibility to translate findings in zebrafish to mice in the field of epilepsy and the potential of the marine environment for ASD discovery. ispartof: MARINE DRUGS vol:17 issue:11 ispartof: location:Switzerland status: published

Muhammad Faisal,* Willi Cawello,* Bjoern B Burckhardt, Stephanie Laer On behalf of LENA Consortium Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany *These authors contributed equally to this work Introduction: Comparative pharmacokinetic (PK) data analysis of drugs administered using developed child-appropriate and market authorized dosage formulation is sparse and is important in pediatric drug development. Objectives: To compare and evaluate any differences in PK of enalapril administered using two treatments of child-appropriate orodispersible minitablets (ODMTs) and market authorized reference tablet formulation (Renitec®) using PK compartment model and validated least square minimization method (LSMM) of parameter estimation. Methods: Full profile data sets were obtained from a phase I clinical trial, whereby three treatments of enalapril, ie, reference tablets with 240 mL water (treatment A), child-appropriate ODMTs with 240 mL (treatment B), and ODMTs dispersed in the mouth with 20 mL water (treatment C), were administered to 24 healthy adult volunteers. Virtual validation analysis was conducted using R program to select accurate and precise LSMM of parameter estimation. For the selection of PK model and estimation of parameters, enalapril data were fitted with one- and two-compartment models with first order of absorption and elimination, with and without incorporated lag time parameter (tlag). The log-transformed PK parameters were statistically compared by the two-sided paired t-test with the level of significance of P

A new tetrahydroindazolylbenzamide derivative has been synthesized, characterized, and evaluated as HIV-inhibitor. The biological data revealed the ability to inhibit HIV proliferation with low cytotoxicity allowing for significant selectivity (EC50 2.77 μM; CC50 118.7 μM; SI = 68). The compound did not inhibit the viral integrase as demonstrated by in vitro studies. QPCR experiments showed that the block of viral replication occurred at early replication steps, prior to integration, profiling it as a late reverse transcription inhibitor. An efficient multistep strategy was adopted for the synthesis of the scaffold, consisting of a sequential ring-opening reaction of oxazol-5-(4H)-one with 1,3-diketone, followed by cyclocondensation with hydrazine and hydrolysis of the nitrile to the desired carboxamide. ispartof: ACS MEDICINAL CHEMISTRY LETTERS vol:10 issue:4 pages:398-401 ispartof: location:United States status: published

Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1-/- mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the α-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates α-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated α-tubulin levels in the hippocampus of Fmr1-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease. ispartof: ACS CHEMICAL NEUROSCIENCE vol:10 issue:3 pages:1679-1695 ispartof: location:United States status: published

Tau, a microtubule-associated protein playing a key role in a group of neurodegenerative diseases such as Alzheimer's disease, spreads throughout the brain, inducing pathology. A model akin to the spreading of prions has been raised owing to similar characteristics of inducing an abnormal protein conformation as a method of self-amplification, spreading protein aggregates over anatomically linked pathways. The search to identify the "seeds" that induce conformational change has received much attention; however, less is known about the mechanisms by which tau is transmitted from cell to cell, so-called "transcellular spreading". In this review, we gather evidence regarding the spreading of tau throughout the brain and provide an overview of methods by which tau can be released from neurons as well as taken up. Furthermore, we bring together mechanisms of neurotoxicity behind tau spreading. Advancing our understanding about the spreading of tau can guide the search for therapeutic options for multiple neurodegenerative diseases aggregating tau. ispartof: CHEMBIOCHEM vol:19 issue:23 pages:2424-2432 ispartof: location:Germany status: published