Ferrocenyl Azoles: Versatile N-Containing Heterocycles and their Anticancer Activities.

The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles.

New insides into chimeric and hybrid azines derivatives with antifungal activity.

During the last decades, five or six member rings azaheterocycles compounds appear to be an extremely valuable source of antifungal agents. Their use seems to be a very attractive solution in antifungal therapy and to overcome antifungal resistance in agriculture. The present review highlights the main results obtained in the field of hybrid and chimeric azine (especially pyridine, quinoline, phenanthroline, bypyridine, naphthyridine and their fused derivatives) derivatives presented in scientific literature from the last 10 years, with emphasis on antifungal activity of the mentioned compounds. A special attention was played to hybrid and chimeric azole-azine class, having in view the high antifungal potential of azoles.

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Machine learning-based QSAR and LB-PaCS-MD guided design of SARS-CoV-2 main protease inhibitors.

The global outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 virus had led to profound respiratory health implications. This study focused on designing organoselenium-based inhibitors targeting the SARS-CoV-2 main protease (Mpro). The ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD) simulations was employed to elucidate plausible paths and conformations of ebselen, a synthetic organoselenium drug, within the Mpro catalytic site. Ebselen effectively engaged the active site, adopting proximity to H41 and interacting through the benzoisoselenazole ring in a π-π T-shaped arrangement, with an additional π-sulfur interaction with C145. In addition, the ligand-based drug design using the QSAR with GFA-MLR, RF, and ANN models were employed for biological activity prediction. The QSAR-ANN model showed robust statistical performance, with an r2training exceeding 0.98 and an RMSEtest of 0.21, indicating its suitability for predicting biological activities. Integration the ANN model with the LB-PaCS-MD insights enabled the rational design of novel compounds anchored in the ebselen core structure, identifying promising candidates with favorable predicted IC50 values. The designed compounds exhibited suitable drug-like characteristics and adopted an active conformation similar to ebselen, inhibiting Mpro function. These findings represent a synergistic approach merging ligand and structure-based drug design; with the potential to guide experimental synthesis and enzyme assay testing.

Synthesis, Antimicrobial Evaluation, and Interaction of Emodin Alkyl Azoles with DNA and HSA.

OBJECTIVE: This study aimed to overcome the growing antibiotic resistance. Moreover, the new series of emodin alkyl azoles were synthesized. METHOD: The novel emodin alkyl azoles were synthesized using commercial emodin and azoles by alkylation. The NMR and HRMS spectra were employed to confirm the structures of novel prepared compounds. The in vitro antibacterial and antifungal activities of the prepared emodin compounds were studied by the 96-well plate method. The binding behavior between emodin 4-nitro imidazole compound 3c and S. aureus DNA was researched using an ultraviolet-visible spectrophotometer. Furthermore, fluorescence spectrometry was used to explore the interaction with human serum albumin (HSA). RESULTS: The in vitro antimicrobial results displayed that compound 3c gave relatively strong activities with MIC values of 4-16 µg/mL. Notably, this compound exhibited 2-fold more potent activity against S. aureus (MIC = 4 µg/mL) and E. coli (MIC = 8 µg/mL) strains than clinical drug Chloromycin (MIC = 8 and 16 µg/mL). The UV-vis absorption spectroscopy showed that 4-nitro imidazole emodin 3c could form the 3c-DNA complex by intercalating into S. aureus DNA, inhibiting antimicrobial activities. The simulation results displayed that the emodin 3c and DNA complex were formed by hydrogen bonds. The spectral experiment demonstrated that compound 3c could be transported by human serum albumin (HSA) via hydrogen bonds. The molecular simulation found that the hydroxyl group and the nitroimidazole ring of the emodin compound showed an important role in transportation behavior. CONCLUSION: This work may supply useful directions for the exploration of novel antimicrobial agents.

Structure-Guided Discovery of the Novel Covalent Allosteric Site and Covalent Inhibitors of Fructose-1,6-Bisphosphate Aldolase to Overcome the Azole Resistance of Candidiasis.

Fructose-1,6-bisphosphate aldolase (FBA) represents an attractive new antifungal target. Here, we employed a structure-based optimization strategy to discover a novel covalent binding site (C292 site) and the first-in-class covalent allosteric inhibitors of FBA from Candida albicans (CaFBA). Site-directed mutagenesis, liquid chromatography-mass spectrometry, and the crystallographic structures of APO-CaFBA, CaFBA-G3P, and C157S-2a4 revealed that S268 is an essential pharmacophore for the catalytic activity of CaFBA, and L288 is an allosteric regulation switch for CaFBA. Furthermore, most of the CaFBA covalent inhibitors exhibited good inhibitory activity against azole-resistant C. albicans, and compound 2a11 can inhibit the growth of azole-resistant strains 103 with the MIC80 of 1 µg/mL. Collectively, this work identifies a new covalent allosteric site of CaFBA and discovers the first generation of covalent inhibitors for fungal FBA with potent inhibitory activity against resistant fungi, establishing a structural foundation and providing a promising strategy for the design of potent antifungal drugs.

Heat shock protein 90 (Hsp90)/Histone deacetylase (HDAC) dual inhibitors for the treatment of azoles-resistant Candida albicans.

Clinical treatment of candidiasis has suffered from increasingly severe drug resistance and limited efficacy. Thus, novel strategies to deal with drug resistance are highly desired to develop effective therapeutic agents. Herein, dual inhibition of heat shock protein 90 (Hsp90) and histone deacetylase (HDAC) was validated as a new strategy to potentiate efficacy of fluconazole against resistant Candida albicans infections. The first generation of Hsp90/HDAC dual inhibitors were designed as synergistic enhancers to treat azoles-resistant candidiasis. In particular, compound J5 exhibited fungal-selective inhibitory effects on Hsp90 and HDACs, leading to low toxicity and excellent in vitro (FICI = 0.266) and in vivo synergistic antifungal potency to treat fluconazole resistant candidiasis. Antifungal-mechanistic investigation revealed that compound J5 suppressed important virulence factors and down-regulated expression of resistance-associated genes. Therefore, Hsp90/HDAC dual inhibitors represent a new strategy for the development of novel antifungal therapeutics to combat azole-resistant candidiasis.

Recent Trends in the Design, Synthesis, Spectroscopic Behavior, and Applications of Benzazole-Based Molecules with Solid-State Luminescence Enhancement Properties.

Molecules that exhibit solid-state luminescence enhancement, i.e. the rare property to be more strongly emissive in the solid state than in solution, find an increasing number of applications in the fields of optoelectronic and nanophotonic devices, sensors, security papers, imaging, and theranostics. Benzazole (BZ) heterocycles are of particular value in this context. The simple enlargement of their π-electron system using a -C=C-Ar or -N=C-Ar moiety is enough for intrinsic solid-state luminescence enhancement (SLE) properties to appear. Their association with a variety of polyaromatic motifs leads to SLE-active molecules that frequently display attractive electroluminescent properties and are sensitive to mechanical stimuli. The excited-state intramolecular proton transfer (ESIPT) process that takes place in some hydroxy derivatives reinforces the SLE effect and enables the development of new sensors based on a protection/deprotection strategy. BZ may also be incorporated into frameworks that are prototypical aggregation-induced enhancement (AIE) luminogens, such as the popular tetraphenylethene (TPE), leading to materials with excellent optical and electroluminescent performance. This review encompasses the various ways to use BZ units in SLE systems. It underlines the significant progresses recently made in the understanding of the photophysical mechanisms involved. A brief overview of the synthesis shows that BZ units are robust building blocks, easily incorporated into a variety of structures. Generally speaking, we try to show how these small heterocycles may offer advantages for the design of increasingly efficient luminescent materials.

Copper-Catalyzed Cross-Coupling of Benzylic C-H Bonds and Azoles with Controlled N-Site Selectivity.

Azoles are important motifs in medicinal chemistry, and elaboration of their structures via direct N-H/C-H coupling could have broad utility in drug discovery. The ambident reactivity of many azoles, however, presents significant selectivity challenges. Here, we report a copper-catalyzed method that achieves site-selective cross-coupling of pyrazoles and other N-H heterocycles with substrates bearing (hetero)benzylic C-H bonds. Excellent N-site selectivity is achieved, with the preferred site controlled by the identity of co-catalytic additives. This cross-coupling strategy features broad scope for both the N-H heterocycle and benzylic C-H coupling partners, enabling application of this method to complex molecule synthesis and medicinal chemistry.

Ebselen and Analogues: Pharmacological Properties and Synthetic Strategies for Their Preparation.

Ebselen is the leader of selenorganic compounds, and starting from its identification as mimetic of the key antioxidant enzyme glutathione peroxidase, several papers have appeared in literature claiming its biological activities. It was the subject of several clinical trials and it is currently in clinical evaluation for the treatment of COVID-19 patients. Given our interest in the synthesis and pharmacological evaluation of selenorganic derivatives with this review, we aimed to collect all the papers focused on the biological evaluation of ebselen and its close analogues, covering the timeline between 2016 and most of 2021. Our analysis evidences that, even if it lacks specificity when tested in vitro, being able to bind to every reactive cysteine, it proved to be always well tolerated in vivo, exerting no sign of toxicity whatever the administered doses. Besides, looking at the literature, we realized that no review article dealing with the synthetic approaches for the construction of the benzo[d][1,2]-selenazol-3(2H)-one scaffold is available; thus, a section of the present review article is completely devoted to this specific topic.

Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles.

A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.

Synthesis and Antibacterial Activity of New Azole, Diazole and Triazole Derivatives Based on p-Aminobenzoic Acid.

The p-aminobenzoic acid was applied for the synthesis of substituted 1-phenyl-5-oxopyrrolidine derivatives containing benzimidazole, azole, oxadiazole, triazole, dihydrazone, and dithiosemicarbazide moieties in the structure. All the obtained compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Salmonella enteritidis, Escherichia coli, and Pseudomonas aeruginosa by using MIC and MBC assays. This study showed a good bactericidal activity of γ-amino acid and benzimidazoles derivatives. The antimicrobial activity of the most promising compounds was higher than ampicillin. Furthermore, two benzimidazoles demonstrated good antimicrobial activity against L. monocytogenes (MIC 15.62 µg/mL) that was four times more potent than ampicillin (MIC 65 µg/mL). Further studies are needed to better understand the mechanism of the antimicrobial activity as well as to generate antimicrobial compounds based on the 1-phenyl-5-oxopyrrolidine scaffold.

Development of novel anti-infective and antioxidant azole hybrids using a wet and dry approach.

Background: Considering emerging drug resistance in microbes, this work is focused on the synthesis of azole hybrids as novel antimicrobials. Materials & methods: The triazole derivatives were prepared using azide alkyne cycloaddition reaction. The antimicrobial potential of these compounds was evaluated by serial dilution method. Results: A series of azole hybrids containing benzimidazole-1,2,3-triazole skeleton was designed and synthesized via click reaction. Compound 4s showed notable antimicrobial activity against Staphylococcus aureus and Candida albicans (MIC 0.0165 µmol/ml), and 4q gives remarkable radical scavenging activity (IC50 0.0092 µmol/ml). The compounds 4a, 4k, 4o, 4s, 4x. 4m, 4n, 4s, 4t and 4x are commendable antibacterial and antifungal molecules, even better than established drugs. Molecular docking reveals that compound 4s binds with tyrosyl-tRNA synthetase residues through two H-bonds. Conclusion: Compounds 4s and 4k may be considered valuable lead compounds for further optimization as antimicrobial drugs.

Isatin-derived azoles as new potential antimicrobial agents: Design, synthesis and biological evaluation.

Novel antibiotics are forced to be developed on account of multidrug-resistant bacteria with serious threats to human health. This work developed isatin-derived azoles as new potential antimicrobial agents. Bioactive assay revealed that isatin hybridized 1,2,4-triazole 7a exhibited excellent inhibitory activity against E. coli ATCC 25,922 with an MIC value of 1 µg/mL, which was 8-fold more potent than reference drug norfloxacin. The active molecule 7a possessed the ability to kill some bacteria and fungi as well as displayed low propensity to induce resistance towards E. coli ATCC25922. Preliminary mechanism investigation indicated that hybrid 7a might block deoxyribonucleic acid (DNA) replication by intercalating with DNA and possibly interacting with DNA polymerase III, thus exerting its antimicrobial potency.

Catalytic and highly regenerable aminic organoselenium antioxidants with cytoprotective effects.

Novel N-methylated ebselenamine antioxidants were prepared from the corresponding diselenides with iodomethane. All ebselenamines showed excellent chain-breaking and glutathione peroxidase (GPx)-like activities. They could also inhibit lipid peroxidation much more efficiently than α-tocopherol. They could also mimic the functions of the GPx-enzymes nearly two times better than ebselen in the coupled reductase assay. Also, they were found to scavenge the ROS produced at low concentration (10 µM) with low toxicity effects and could have therapeutic potential against autoxidation. It is anticipated that these compounds could potentially be used against several diseases caused by autoxidation, and thus provide protection from cell death to mammals.

Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.

Design and Synthesis of New Antifungals Based on N-Un-substituted Azoles as 14α Demethylase Inhibitor.

OBJECTIVE: Azole antifungal agents, which are widely used as antifungal antibiotics, inhibit cytochrome P450 sterol 14α-demethylase (CYP51). Nearly all azole antifungal agents are Nsubstituted azoles. In addition, an azolylphenalkyl pharmacophore is uniquely shared by all azole antifungals. Due to the importance of nitrogen atom of azoles (N-3 of imidazole and N-4 of triazole) in coordination with heme in the binding site of the enzyme, here a group of N- un-substituted azoles in which both nitrogen are un-substituted was reported. MATERIALS AND METHODS: Designed compounds were synthesized by the reaction of imidazole-4- carboxaldehyde with appropriate arylamines and subsequently reduced to desired amine derivatives. Antifungal activity against Candida albicans and Saccharomyces cervisiae was done using a broth micro-dilution assay. Docking studies were done using AutoDock. RESULTS: Antimicrobial evaluation revealed that some of these compounds exhibited moderate antimicrobial activities against tested pathogenic fungi, wherein compounds 3, 7, and 8 were potent. Docking studies propose that all of the prepared azoles interacted with 14α-DM, wherein azoleheme coordination played the main role in drug-receptor interaction. CONCLUSION: Our results offer some useful references for molecular design performance or modification of this series of compounds as a lead compound to discover new and potent antimicrobial agents.

Photoredox chemistry in the synthesis of 2-aminoazoles implicated in prebiotic nucleic acid synthesis.

Prebiotically plausible ferrocyanide-ferricyanide photoredox cycling oxidatively converts thiourea to cyanamide, whilst HCN is reductively homologated to intermediates which either react directly with the cyanamide giving 2-aminoazoles, or have the potential to do so upon loss of HCN from the system. Thiourea itself is produced by heating ammonium thiocyanate, a product of the reaction of HCN and hydrogen sulfide under UV irradiation.

N-Trifluoromethyl Amines and Azoles: An Underexplored Functional Group in the Medicinal Chemist's Toolbox.

Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, N-trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of N-trifluoromethyl amines and azoles, determined their stability in aqueous media, and investigated their properties. We show that N-trifluoromethyl amines are prone to hydrolysis, whereas N-trifluoromethyl azoles have excellent aqueous stability. Compared to their N-methyl analogues, N-trifluoromethyl azoles have a higher lipophilicity and can show increased metabolic stability and Caco-2 permeability. Furthermore, N-trifluoromethyl azoles can serve as bioisosteres of N-iso-propyl and N-tert-butyl azoles. Consequently, we suggest that N-trifluoromethyl azoles are valuable substructures to be considered in medicinal chemistry.

Site mapping and small molecule blind docking reveal a possible target site on the SARS-CoV-2 main protease dimer interface.

The SARS-CoV-2 virus is causing COVID-19 resulting in an ongoing pandemic with serious health, social, and economic implications. Much research is focused in repurposing or identifying new small molecules which may interact with viral or host-cell molecular targets. An important SARS-CoV-2 target is the main protease (Mpro), and the peptidomimetic α-ketoamides represent prototypical experimental inhibitors. The protease is characterised by the dimerization of two monomers each which contains the catalytic dyad defined by Cys145 and His41 residues (active site). Dimerization yields the functional homodimer. Here, our aim was to investigate small molecules, including lopinavir and ritonavir, α-ketoamide 13b, and ebselen, for their ability to interact with the Mpro. The sirtuin 1 agonist SRT1720 was also used in our analyses. Blind docking to each monomer individually indicated preferential binding of the ligands in the active site. Site-mapping of the dimeric protease indicated a highly reactive pocket in the dimerization region at the domain III apex. Blind docking consistently indicated a strong preference of ligand binding in domain III, away from the active site. Molecular dynamics simulations indicated that ligands docked both to the active site and in the dimerization region at the apex, formed relatively stable interactions. Overall, our findings do not obviate the superior potency with respect to inhibition of protease activity of covalently-linked inhibitors such as α-ketoamide 13b in the Mpro active site. Nevertheless, along with those from others, our findings highlight the importance of further characterisation of the Mpro active site and any potential allosteric sites.

Insight into Mechanism of Action of Anticancer Benzazoles.

BACKGROUND: Targeting the DNA topoisomerase II enzyme (topo II) is a promising anticancer treatment approach. TopoII controls and modifies the topological states of DNA and plays key roles in DNA replication, transcription, and chromosome segregation. The DNA binding and cleavage domain is one of the active sites of this enzyme. It is known that topoisomerase inhibitors, also known as topoisomerase poisons, bind to the transient enzyme-DNA complex and inhibit the religation of DNA, generating single- and double-stranded breaks that harm the integrity of the genome. This ultimately leads to the accumulation of DNA strand breaks and cell death. METHODS: Our previously synthesized benzazole derivatives were tested for their eukaryotic DNA topoisomerase II inhibitory activity in a cell-free system. Their interactions with the enzyme were studied by carrying out molecular docking studies using and comparing two different docking programs. RESULTS: The results of the docking studies clarified binding modes of these compounds to the topoisomerase II enzyme. CONCLUSION: This study also provides guidelines to design novel and more potent antitumor agents functioning as human topoisomerase II enzyme inhibitors.