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Our aim is to identify new small molecules with antimicrobial potential, especially against colistin-resistant (Col-R) Acinetobacter baumannii and Escherichia coli. After initial hits identification by fingerprint similarity, MIC of 24 heterocyclic derivatives for A. baumannii and E. coli reference strains, and bactericidal activity of selected thiophenes against Col-R strains were determined. We analyzed changes in bacterial membrane permeability and the OMPs profile. Additionally, we determined bacterial adherence to host cells and performed molecular docking studies to assess their binding to bacterial targets. The compounds’ MICs ranged from 4 to >64 mg/L. Thiophene derivatives 4, 5 and 8 exhibited MIC50 values between 16 and 32 mg/L for Col-R A. baumannii and 8 and 32 mg/L for Col-R E. coli. The time-kill curve assay demonstrated that thiophenes 4 and 8 had bactericidal effects against Col-R A. baumannii and E. coli. Furthermore, treatment with them resulted in increased membrane permeabilization and reduced adherence of these isolates to host cells. Finally, the docking studies showed a stronger binding affinity to CarO1 and Omp33 of A. baumannii and OmpW and OmpC of E. coli. These findings indicate that thiophene derivatives possess antibacterial activity against Col-R A. baumannii and E. coli, suggesting that they may enhance the repertoire of drug treatments against bacteria. [ABSTRACT FROM AUTHOR]

Chemical libraries have become of utmost importance to boost drug discovery processes. It is widely accepted that the quality of a chemical library depends, among others, on its availability and chemical diversity which help in rising the chances of finding good hits. In this regard, our group has developed a source for useful chemicals named Medicinal and Biological Chemistry (MBC) library. It originates from more than 30 years of experience in drug design and discovery of our research group and has successfully provided effective hits for neurological, neurodegenerative and infectious diseases. Moreover, in the last years, the European research infrastructure for chemical biology EU-OPENSCREEN has generated the European Chemical Biology library (ECBL) to be used as a source of hits for drug discovery. Here we present and discuss the updated version of the MBC library (MBC v.2022), enriched with new scaffolds and containing more than 2,500 compounds together with ECBL that collects about 100,000 small molecules. To properly address the improved potentialities of the new version of our MBC library in drug discovery, up to 44 among physicochemical and pharmaceutical properties have been calculated and compared with those of other well-known publicly available libraries. For comparison, we have used ZINC20, DrugBank, ChEMBL library, ECBL and NuBBE along with an approved drug library. Final results allowed to confirm the competitive chemical space covered by MBC v.2022 and ECBL together with suitable drug-like properties. In all, we can affirm that these two libraries represent an interesting source of new hits for drug discovery. [ABSTRACT FROM AUTHOR]

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness. Author summary: Since early 2020, the trajectory of the COVID-19 pandemic has mostly been shaped by the appearance of novel variants of the SARS-CoV-2 virus. Accordingly, much of the scientific effort has been directed toward the question of explaining, understanding, and predicting the evolutionary fate of individual mutations in the viral genome. In this article, we focus on A222V, a particular mutation in the Spike protein that emerged in Spain in mid-2020 and reappeared independently in the AY.4.2 subvariant of Delta one year later. As reemerging mutations often indicate an evolutionary advantage, we explored potential mechanisms linking A222V to biologically relevant outcomes. Using serological, functional, structural, and computational approaches, we identified key molecular-level differences conferred by A222V that potentially explain its repeated emergence in different genetic backgrounds. Our results point to subtle changes in the dynamic behavior of the receptor-binding domain in the binding-competent "up" conformation, ones that affect receptor binding itself, but can also act synergistically with other mutations by changing the accessibility of key residues involved in molecular recognition. [ABSTRACT FROM AUTHOR]

Many (poly‐)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid‐β 42 (Aβ42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Aβ42, which adopts different folds, affecting the propensity to populate fibril‐like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Aβ42 aggregation inhibition, glutamate‐induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV‐2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5 μm (83 % cell survival), whereas curcumin only showed very low protection at 10 μm (21 % cell survival). [ABSTRACT FROM AUTHOR]

In this report, a series of novel piperidine-substituted thiophene[3,2- d pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC 50 ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure–activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection. Compound 26 exhibited potent activity against wild-type and a panel of single mutations with an EC 50 ranging from 6.02 to 23.9 nmol/L. Furthermore, 26 exhibited favorable PK profiles and with a bioavailability of 33.8%. These results demonstrated that 26 holds great promise as a potential HIV-1 drug candidate. Image 1 [ABSTRACT FROM AUTHOR]

Abstract: Inhibition of abnormal protein self‐aggregation is an attractive strategy against amyloidogenic diseases, but has found limited success due to the complexity of protein self‐assembly, the absence of fully reproducible aggregation assays, and the scarce knowledge of the inhibition mechanisms by small molecules. In this context, catechol‐containing compounds may lead to covalent adducts with amyloid fibrils that interfere with the aggregation process. In particular, the covalent adduct formed between the oxidized form of (+)‐taxifolin and an β‐amyloid (Aβ42) suggests the involvement of a specific recognition motif that enables the chemical reaction with Aβ42. In this study, we have examined the mechanisms implicated in the aza‐Michael addition of the o‐quinone species of (+)‐taxifolin with Aβ42 fibrils. The results support the binding of (+)‐taxifolin to the hydrophobic groove delimited by the edges defined by Lys16 and Glu22 residues in the fibril. The chemical reaction proceeds through the nucleophilic attack of the deprotonated amino group of a Lys16 residue in a process activated by the interaction between the o‐quinone ring with a vicinal Lys16 residue, as well as by a water‐assisted proton transfer, which is the rate‐limiting step of the reaction. This specific inhibition mechanism, which may explain the enhanced anti‐aggregating activity of oxidized flavonoids compared to fresh compounds, holds promise for developing disease‐modifying therapies. [ABSTRACT FROM AUTHOR]

New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized andin vitrotested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that6cwas a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for6cshowed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound6cis positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130. [ABSTRACT FROM PUBLISHER]

In the Financial Disclosure, the number for the grant awarded by EPIDNA is incorrect. Reference 1 Ginex T, Marco-Marín C, Wieczór M, Mata CP, Krieger J, Ruiz-Rodriguez P, et al. (2022) The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation. [Extracted from the article]

Since the development of structure-activity relationships about 50 years ago, 3D-QSAR methods belong to the most refined ligand-based in silico techniques for prediction of biological data using physicochemical molecular fields. In this scenario, this study reports the development and validation of quantum mechanical (QM)-based hydrophobic descriptors derived from the parametrized MST continuum solvation model to be used in 3D-QSAR studies within the framework of the Hydrophobic Pharmacophore (HyPhar) method. To this end, five sets of compounds reported in the literature (dopamine D2/D4 antagonists, antifungal 2-aryl-4-chromanones, and inhibitors of GSK-3, cruzain and thermolysin) have been revisited. The results derived from the QM/MST-based hydrophobic descriptors have been compared with previous CoMFA and CoMSIA studies, and examined in light of the available X-ray crystallographic structures of the targets. The analysis reveals that the combination of electrostatic and nonelectrostatic components of the octanol/water partition coefficient yields pharmacophoric models fully comparable with the predictive potential of standard 3D-QSAR techniques. Moreover, the graphical representation of the hydrophobic maps provides a direct linkage with the pattern of interactions found in crystallographic structures. Overall, the introduction of the QM/MST-based descriptors, which could be easily adapted to other continuum solvation formalisms, paves the way to novel computational strategies for disclosing structure-activity relationships in drug design. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A crucial limit toin silicopreliminary toxicological evaluations in the “food safety” area is the lack of a specific, efficient and available free dataset of 3D small molecules. In this direction, we present the first version of FADB (Food Additives Data Base), a suitable and freely available food additives dataset. FADB is the 3D version of the EAFUS (Everything Added to Food in the United States) list, a sum of WHO, FAO food additive databases and could be a useful starting material in preliminary stages of toxicological assessments. Molecules in FADB are represented through several chemical and 1D identifies, physical properties and 3D (SD and Mol2 file) file formats. FADB also contains important information about functional uses of chemicals as food additives. The aim of the work is to put together substances potentially relevant to food into a “computational” library for virtual screening and docking studies with interesting scenarios for toxicology. [ABSTRACT FROM PUBLISHER]

The unprecedent situation generated by the COVID-19 global emergency has prompted us to actively work to fight against this pandemic by searching for repurposable agents among FDA approved drugs to shed light into immediate opportunities for the treatment of COVID-19 patients. In the attempt to proceed toward a proper rationalization of the search for new antivirals among approved drugs, we carried out a hierarchical in silico/in vitro protocol which successfully combines virtual and biological screening to speed up the identification of host-directed therapies against COVID-19 in an effective way. To this end a multi-target virtual screening approach focused on host-based targets related to viral entry, followed by the experimental evaluation of the antiviral activity of selected compounds, has been carried out. As a result, five different potentially repurposable drugs interfering with viral entry—cepharantine, clofazimine, metergoline, imatinib and efloxate—have been identified. [ABSTRACT FROM AUTHOR]

Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several compounds, such as 6 , 14 , 15 , 21 , 30 , and 33 , were found to be potent inhibitors against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant strains at low nanomolar levels. Detailed structure-activity relationships were obtained by utilizing the variation of moieties within the corresponding pharmacophores. In vitro metabolic stability profiles and some drug-like properties of selected compounds were assessed, furnishing the preliminary structure-metabolic stability relationships. Furthermore, molecular modeling studies elucidated the binding modes of compounds 6 , 15 , 21 , and 30 in the binding pocket of WT, E138K, K103N, or Y181C HIV-1 RTs. These promising compounds can be used as lead compounds and warrant further structural optimization to yield more active HIV-1 inhibitors.

Introduction: Despite the current interest caused by SARS-Cov-2, influenza continues to be one of the most serious health concerns, with an estimated 1 billion cases across the globe, including 3-5 million severe cases and 290,000-650,000 deaths worldwide. Areas covered: This manuscript reviews the efforts made in the development of small molecules for the treatment of influenza virus, primarily focused on patent applications in the last 5 years. Attention is paid to compounds targeting key functional viral proteins, such as the M2 channel, neuraminidase, and hemagglutinin, highlighting the evolution toward new ligands and scaffolds motivated by the emergence of resistant strains. Finally, the discovery of compounds against novel viral targets, such as the RNA-dependent RNA polymerase, is discussed. Expert opinion: The therapeutic potential of antiviral agents is limited by the increasing presence of resistant strains. This should encourage research on novel strategies for therapeutic intervention. In this context, the discovery of arbidol and JNJ7918 against hemagglutinin, and current efforts on RNA-dependent RNA polymerase have disclosed novel opportunities for therapeutic treatment. Studies should attempt to expand the therapeutic arsenal of anti-flu agents, often in combined therapies, to prevent future health challenges caused by influenza virus. Abbreviations: AlphaLISA: amplified luminescent proximity homogeneous assay; HA: hemagglutinin; NA: neuraminidase; RBD: receptor binding domain; RdRp: RNA-dependent RNA polymerase; SA: sialic Acid; TBHQ: tert-butyl hydroquinone; TEVC: two-electrode voltage clamp.

In this report, a series of novel piperidine-substituted thiophene[3,2- d ]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2 . The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC 50 ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure-activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection., (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC 50(WT) = 0.0035 μM, EC 50(E138K) = 0.0075 μM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC 50 ≥ 173 μM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/subacute toxicities at doses of 2000 mg·kg -1 /50 mg·kg -1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.

Alzheimer's disease (AD) is the main cause of dementia in people over 65 years. One of the major culprits in AD is the self-aggregation of amyloid-β peptide (Aβ), which has stimulated the search for small molecules able to inhibit Aβ aggregation. In this context, we recently reported a simple, but effective in vitro cell-based assay to evaluate the potential antiaggregation activity of putative Aβ aggregation inhibitors. In this work this assay was used together with docking and molecular dynamics simulations to analyze the anti-Aβ aggregation activity of several naturally occurring flavonoids and phenolic compounds. The results showed that rosmarinic acid, melatonin, and o-vanillin displayed zero or low inhibitory capacity, curcumin was found to have an intermediate inhibitory potency, and apigenin and quercetin showed potent antiaggregation activity. Finally, the suitability of the combined in vitro cell-based/in silico approach to distinguish between active and inactive compounds was further assessed for an additional set of flavonols and dihydroflavonols.

Foodstuff could be a vector for naturally occurring and/or unwanted dangerous substances that can act either as they are or after their bioactivation. The scientific community agrees that the metabolic activity of chemicals should be taken into account for proper risk assessment. Unfortunately, the in vitro evaluation of a metabolic panel and analytical/biochemical detection in food-safety assessment are very expensive and challenging because of the abundance of data to analyze. In this context, properly validated computational protocols could be a useful tool for making metabolic and binding/activity predictions. This strategy has been applied to thioxanthone photoinitiators (TX), identified as food contaminants, especially in infant formulas, as reported by the European Food Safety Authority in 2005. Their lipophilicity suggests rapid hepatic metabolism, but the currently available data only concern 2-ITX. We have predicted phase I metabolites for the TX class of compounds and defined their binding affinity for the AR ligand-binding pocket using a local model based on available information about metabolism and AR activity. Some metabolites should undergo further in vitro or/and in vivo toxicological evaluations because they have proved to be suitable as ligands for AR.