TY - JOUR

T1 - Conjugation of a 5-nitrofuran-2-oyl moiety to aminoalkylimidazoles produces non-toxic nitrofurans that are efficacious in vitro and in vivo against multidrug-resistant Mycobacterium tuberculosis

AU - Krasavin, Mikhail

AU - Lukin, Alexei

AU - Vedekhina, Tatiana

AU - Manicheva, Olga

AU - Dogonadze, Marine

AU - Vinogradova, Tatiana

AU - Zabolotnykh, Natalia

AU - Rogacheva, Elizaveta

AU - Kraeva, Liudmila

AU - Yablonsky, Piotr

PY - 2018/9/5

Y1 - 2018/9/5

N2 - Within the general nitrofuran carboxamide chemotype, chimera derivatives incorporating diversely substituted imidazoles attached via an alkylamino linker were synthesized. Antimycobacterial evaluation against drug-sensitive M. tuberculosis H37Rv strain identified five active druglike compounds which were further profiled against patient-derived M. tuberculosis strains in vitro. One of the compounds displayed promising potent activity (MIC 0.8 μg/mL) against one of such strains otherwise resistant to such first- and second-line TB therapies as streptomycin, isoniazid, rifampicin, ethambutol, kanamycin, ethionamide, capreomycin and amikacin. The compound was shown to possess low toxicity for mice (LD50 = 900.0 ± 83.96 mg/kg) and to be similarly efficacious to etambutol, in the mouse model of drug-sensitive tuberculosis, and to neurotoxic cycloserine in mice infected with MDR tuberculosis.

AB - Within the general nitrofuran carboxamide chemotype, chimera derivatives incorporating diversely substituted imidazoles attached via an alkylamino linker were synthesized. Antimycobacterial evaluation against drug-sensitive M. tuberculosis H37Rv strain identified five active druglike compounds which were further profiled against patient-derived M. tuberculosis strains in vitro. One of the compounds displayed promising potent activity (MIC 0.8 μg/mL) against one of such strains otherwise resistant to such first- and second-line TB therapies as streptomycin, isoniazid, rifampicin, ethambutol, kanamycin, ethionamide, capreomycin and amikacin. The compound was shown to possess low toxicity for mice (LD50 = 900.0 ± 83.96 mg/kg) and to be similarly efficacious to etambutol, in the mouse model of drug-sensitive tuberculosis, and to neurotoxic cycloserine in mice infected with MDR tuberculosis.

KW - Antitubercular

KW - Chimera drug design

KW - Druglikeness

KW - Imidazoles

KW - Multidrug resistant

KW - Mycobacterium tuberculosis

KW - Nitrofurans

KW - Selective antimycobacterial activity

KW - PERMEABILITY

KW - ANTITUBERCULOSIS AGENTS

KW - SUSCEPTIBILITY

KW - ANTIBACTERIAL AGENTS

KW - IDENTIFICATION

KW - BACTERICIDAL ACTIVITY

KW - DRUGS

UR - http://www.scopus.com/inward/record.url?scp=85052612769&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2018.08.068

DO - 10.1016/j.ejmech.2018.08.068

M3 - Article

AN - SCOPUS:85052612769

VL - 157

SP - 1115

EP - 1126

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -