benzofurans and Tuberculosis--Multidrug-Resistant

A series of 4H-chromen-4-one derivatives obtained by scaffold morphing of the benzofuran compound, TAM16, were tested for antitubercular activity. Compound 8d was active against drug-sensitive and multidrug-resistant tuberculosis. A preliminary druggability evaluation showed that compound 8d displayed favorable mouse and human microsomal stability, low cytotoxicity, and acceptable oral bioavailability. An in vivo study indicated that compound 8d exhibited modest efficacy in an acute mouse model of TB after 3 weeks of treatment. Thus, 8d is a promising antituberculosis lead compound.

Topics: Animals; Antitubercular Agents; Benzofurans; Benzopyrans; Drug Design; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Microsomes, Liver; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis, Multidrug-Resistant

Tuberculosis remains a serious public health problem, with nine million cases being reported annually. Treatment with antibiotics is the most effective mechanism to control this disease, although the increase in cases with resistant strains, co-infection with HIV, and the long duration of treatment has established the need to develop new drugs. Here we show the activity of usnic acid against susceptible and resistant Mycobacterium tuberculosis strains and against nontuberculous mycobacteria. Further, we did not identify any contribution of efflux in innate resistance to usnic acid.

Topics: Anti-Bacterial Agents; Benzofurans; Calcium Channel Blockers; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Ionophores; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Tuberculosis, Multidrug-Resistant; Verapamil