DNA gyrase inhibitors(Southwest University)

Two series of antibacterial agents, 1,2,3-triazole and aminopyrimidine benzimidazole hybrids, were designed, synthesized, and characterized by IR, NMR, Mass spectroscopy, and X-ray crystallography studies. The biological studies revealed that compounds 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 8d, 8e, 9d, 9e, 9f, 9h, 9j, and 9k exhibited significant antibacterial activity in vitro compared to the standard drug ciprofloxacin, against Gram-positive and Gram-negative bacterial strains. The study of hemotoxicity displayed a negligible toxicity profile for all the compounds. Furthermore, the mechanistic insights predicted via molecular docking studies on DNA gyrase revealed (Glide Scores) that compounds 5c and 5f possess better affinity within the active domain of DNA gyrase, which was further corroborated using molecular dynamics followed by direct DNA gyrase-based inhibition assays. Compound 5f was the most potent, while 5c showed an equipotent inhibition compared to a standard drug.

Developing new classes of drugs that are active against infections caused by Mycobacterium tuberculosis is a priority for treating and managing this deadly disease. Here, we describe screening a small library of 20 DNA gyrase inhibitors and identifying new lead compounds. Three structurally diverse analogues were identified with minimal inhibitory concentrations of 0.125 μg/mL against both drug-susceptible and drug-resistant strains of M. tuberculosis. These lead compounds also demonstrated antitubercular activity in ex vivo studies using infected THP-1 macrophages with minimal cytotoxicity in THP-1, HeLa, and HepG2 cells (IC₅₀ ≥ 128 μg/mL). The molecular target of the lead compounds was validated through biochemical studies of select analogues with purified M. tuberculosis gyrase and the generation of resistant mutants. The lead compounds were assessed in combination with bedaquiline and pretomanid to determine the clinical potential, and the select lead (158) demonstrated in vivo efficacy in an acute model of TB infection in mice, reducing the lung bacterial burden by approximately 3 log₁₀ versus untreated control mice. The advancement of DNA gyrase inhibitors expands the field of innovative therapies for tuberculosis and may offer an alternative to fluoroquinolones in future therapeutic regimens.