Gui-Xin Cai

Recent developments in azole compounds as antibacterial and antifungal agents

Azole compounds are an important class of nitrogen heterocycles with electron-rich property. This special structure endows azole-based derivatives easily bind with the enzymes and receptors in organisms through noncovalent interactions such as hydrogen bonds, coordination bonds, ion-dipole, cation-π,π-π stacking and hydrophobic effect as well as van der Waals force etc., thereby possessing various applications in medicinal chemistry, especially their protrudent effects such as imidazoles and triazoles against fungal strains. The design, synthesis and antimicrobial activity of azole derivatives have been extensively investigated and have become one of the highly active highlights in recent years, and the progress is quite rapid. In particular, a large number of azole-based antibacterial and antifungal agents have been penetratingly studied as candidates and even some of them have been used in clinic, which have shown the great potential and development value of azole compounds. Based on our researches on azole compounds and referring to other literature, this work scientifically reviewed the researches and developments of azole-based compounds as antibacterial and antifungal agents, including oxazole, imidazole, benzimidazole, triazole, benzotriazole, pyrazole, thiazole, carbazole as well as tetrazole in recent three years. It is hopeful that azole compounds may continue to serve as an important direction for the exploitation of azole-based antibacterial and antifungal drugs with better curative effect, lower toxicity, less side effects, especially fewer resistances and so on.

Synthesis and bioactive evaluation of a novel series of coumarinazoles

A series of novel coumarinazoles were designed, synthesized, and characterized by IR, NMR, MS and HRMS spectra. The bioactive assay for the newly prepared compounds against six bacteria and five fungi manifested that most new compounds exhibited good or even stronger antibacterial and antifungal activities in comparison with reference drugs Chloromycin, Norfloxacin and Fluconazole. Bis-azole alcohols 7a and 7d-e showed better anti-Candida utilis activity than mono-azole derivatives 4a and 4d-e at the tested concentrations, and they were more potent than the clinical Fluconazole. While triazole alcohol 7a gave comparable anti-Candida albicans and anti-Candida mycoderma activity to Fluconazole and better anti-MRSA activity than mono-triazole one 4a and clinical Norfloxacin. 1H-Benzoimidazol-2-ylthio coumarin derivatives 4e and 7e gave the strongest anti-Escherichia coli JM109 efficacy. Oxiran-2-ylmethoxy moiety was found to be a beneficial fragment to improve antibacterial and antifungal activity to some extent.

Current developments in the syntheses of 1,2,4-triazole compounds

Heterocyclic 1,2,4-triazole derivatives possess unusually spacious potentiality as medicinal agents, agricultural chemicals, functional materials, ionic liquids, supramolecular catalysts as well as artificial enzymes and receptors for supramolecular recognition and biomimetic catalysis, and their various researches and developments have been being a quite rapidly developing and active highlight topic with an infinite space. Numerous efforts have been directed toward various types of possible applications of 1,2,4-triazole-based compounds and a lot of important progress has been made, especially their preparations have attracted increasing attention. This review systematically summarized the recent advances in the syntheses of 1,2,4-triazole derivatives, including: (1) Cyclizations to form triazole ring; (2) Transformations of heterocyclic compounds to construct triazole ring; (3) Substitutions on 1,2,4-triazole ring; (4) Structural modifications in side chains of 1,2,4-triazole ring. It was hoped that this review would be helpful for the design and development of highly efficient preparation of 1,2,4-triazole derivatives with various sorts and varieties of extensively potential applications in medicine, agriculture, chemistry, materials, supramolecular sciences and so on.

Novel purine benzimidazoles as antimicrobial agents by regulating ROS generation and targeting clinically resistant Staphylococcus aureus DNA groove

A novel series of purine benzimidazole hybrids were designed and synthesized for the first time with the aim to circumvent the increasing antibiotic resistance. Hexyl appended hybrid 3c gave potent activities against most of the tested bacteria and fungi especially against multidrug-resistant strains Staphylococcus aureus (MIC = 4 µg/mL). Structure-activity relationships revealed that the benzimidazole fragment at the 9-position of purine played an important role in exerting potentially antibacterial activity. Both cell toxicity and ROS generation assays indicated that the purine derivative 3c showed low cytotoxicity and could be used as a safe agent. Molecular modeling suggested that hybrid 3c could bind with the residues of Topo IA through hydrogen bonds and electrostatic interactions. Quantum chemical studies were also performed on the target compound 3c to understand the structural features essential for activity. The active molecule 3c could effectively interact with S. aureus DNA to form 3c-DNA complex through groove binding mode, which might block DNA replication to display their powerful antimicrobial activity.

Discovery of Benzimidazole-Quinolone Hybrids as New Cleaving Agents toward Drug-Resistant Pseudomonas aeruginosa DNA

A series of benzimidazole–quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2‐fluorobenzyl derivative 5 b (ethyl 7‐chloro‐6‐fluoro‐1‐[[1‐[(2‐fluorophenyl)methyl]benzimidazol‐2‐yl]methyl]‐4‐oxo‐quinoline‐3‐carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep‐2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV–DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug‐resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.