Bromomethylthioindole Inspired Carbazole Hybrids as Promising Class of Anti-MRSA Agents

Abstract

Series of N-substituted carbazole analogues bearing an indole ring were synthesized as anti-methicillinresistant Staphylococcus aureus (MRSA) agents from a molecular hybridization approach. The representative compound 19 showed an MIC = 1 μg/mL against a panel of MRSA clinical isolates as it possessed comparable in vitro activities to that of vancomycin. Moreover, compound 19 also exhibited MIC = 1 μg/mL activities against a recent identified Z172 MRSA strain (vancomycin-intermediate and daptomycin-nonsusceptible phenotype) and the vancomycin-resistant Enterococcus faecalis (VRE) strain. In a mouse model with lethal infection of MRSA (4N216), a 75% survival rate was observed after a single dose of compound 19 was intravenously administered at 20 mg/kg. In light of their equipotent activities against different MRSA isolates and VRE strain, the data underscore the importance of designed hybrid series for the development of new N-substituted carbazoles as potential anti-MRSA agents.

Potential Antimicrobial Isopropanol-Conjugated Carbazole Azoles as Dual Targeting Inhibitors of Enterococcus faecalis

“…14 Particularly, aminoalcohols have been announced to exert prominent antibacterial abilities. 15 Currently, azoles with advantages like high therapeutic index, favorable pharmacokinetic parameters, and good safety profile have achieved considerable success in the treatment of infective diseases by interacting with biomacromolecules in microorganisms. 16,17 Structurally simple metronidazole as a combination of alcohol and nitroimidazole exerts excellent inhibitory efficacies against obligate anaerobes, and this remarkable success quickly diverts continuous efforts toward the development of other hydroxyethyl azoles in clinic to treat pathogenic infections.…”

“…Alcohols from natural and artificial sources have long been employed as disinfectants with potent antimicrobial potentiality in daily life because of the ubiquity, convenience, and high efficiency . Particularly, aminoalcohols have been announced to exert prominent antibacterial abilities . Currently, azoles with advantages like high therapeutic index, favorable pharmacokinetic parameters, and good safety profile have achieved considerable success in the treatment of infective diseases by interacting with biomacromolecules in microorganisms. , Structurally simple metronidazole as a combination of alcohol and nitroimidazole exerts excellent inhibitory efficacies against obligate anaerobes, and this remarkable success quickly diverts continuous efforts toward the development of other hydroxyethyl azoles in clinic to treat pathogenic infections. , Some nonclinical hydroxyethyl azoles have also been developed with superior antibacterial or antifungal potencies. , These researches clearly demonstrated the enormous potentiality of hydroxyethyl azole in the antimicrobial aspect.…”

Recent advances in indole dimers and hybrids with antibacterial activity against methicillin‐resistant Staphylococcus aureus

“…The indole–carbazole derivative 27 (MIC: 0.5–2.0 µg/ml) exhibited potential activity against clinical MSSA M056, seven clinical MRSA (M013, N043, C217, Y069, L166, Z234, and 4N216), hospital‐associated MRSA (vancomycin‐intermediate and daptomycin‐nonsusceptible phenotypes), and VRE strains. [ 54 ] In the MRSA 4N216 mouse systemic infection mice model, compound 27a (20 mg/kg, iv) could neutralize MRSA 4N216 infection in an effective manner, resulting in a 75% survival rate as compared with vancomycin (100% survival rate). Moreover, compound 27a (10 mg/kg, iv) showed a longer half‐life ( t 1/2 : 10.3 vs. 0.6 hr) and a larger blood exposure (area under the curve: 20,546 vs. 13,715 ng/ml) than vancomycin (10 mg/kg, iv).…”

Antifungal Exploration of Quinoline Derivatives against Phytopathogenic Fungi Inspired by Quinine Alkaloids

“…A series of 4-quinolinol derivatives with various substitutions on a quinoline ring were evaluated for their antifungal activity, and privileged compound 2,8-bis­(trifluoromethyl)-4-quinolinol ( 3 ) was found to be the most active compound and could be used as a lead compound for further derivatization. Therefore, in this study, inspired by intermediate derivatization methods for agrochemical discovery and application of diversity-oriented synthesis in medicinal chemistry, − four different series of quinoline derivatives were successfully designed and synthesized and their in vitro and in vivo antifungal activities against plant pathogenic fungi were evaluated (Figure ). Moreover, the preliminary mechanism of action of the most effective fungicidal candidate against B.…”