Structure-activity relationship studies on 2,5,6-trisubstituted benzimidazoles targeting Mtb -FtsZ as antitubercular agents

• Published in: MedChemComm Vol. 12; no. 1; pp. 78 - 94
• Main Authors: Haranahalli, Krupanandan, Tong, Simon, Kim, Saerom, Awwa, Monaf, Chen, Lei, Knudson, Susan E, Slayden, Richard A, Singleton, Eric, Russo, Riccardo, Connell, Nancy, Ojima, Iwao
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 01.01.2021; RSC
• Subjects: Antiinfectives and antibacterials; Antitubercular agents; Benzimidazoles; Cell division; Chemistry; Drug development; Intermediates; Libraries; Minimum inhibitory concentration; NMR; Nuclear magnetic resonance; Proteins
• ISSN: 2632-8682; 2040-2503; 2632-8682; 2040-2511
• DOI: 10.1039/d0md00256a

Filamenting temperature sensitive protein Z (FtsZ) is an essential bacterial cell division protein and a promising target for the development of new antibacterial therapeutics. As a part of our ongoing SAR studies on 2,5,6-trisubstituted benzimidazoles as antitubercular agents targeting -FtsZ, a new library of compounds with modifications at the 2 position was designed, synthesized and evaluated for their activity against -H37Rv. This new library of trisubstituted benzimidazoles exhibited MIC values in the range of 0.004-50 μg mL . Compounds , , and showed excellent growth inhibitory activities ranging from 0.004-0.08 μg mL . This SAR study has led to the discovery of a remarkably potent compound (MIC 0.0039 μg mL ; normalized MIC 0.015 μg mL ). Our 3DQSAR model predicted as the most potent compound in the library.