The development of new antitubercular agents for the treatment of infections caused by multidrug-resistant (MDR) is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents that were initially discovered and isolated from a range of species. Recently, C8-linked PBD monomers have been shown to work by inhibiting DNA gyrase and have demonstrated activity against . However, both PBD monomers and dimers are toxic to eukaryotic cells, limiting their development as antibacterial agents. To eliminate the toxicity associated with PBDs and explore the effect of C8-modification with a known antibacterial agent with the same mechanism of action (i.e., ciprofloxacin, a gyrase inhibitor), we synthesized a C8-linked PBD-ciprofloxacin (PBD-CIP, ) hybrid. The hybrid compound displayed minimum inhibitory concentration values of 0.4 or 2.1 μg/mL against drug-sensitive and drug-resistant strains, respectively. A molecular modeling study showed good interaction of compound with wild-type DNA gyrase, suggesting gyrase inhibition as a possible mechanism of action. Compound is a nontoxic combination hybrid that can be utilized as a new scaffold and further optimized to develop new antitubercular agents.
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| http://dx.doi.org/10.1021/acsomega.9b00834 | DOI Listing |
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