Investigating FadD32 as a Target for 7-Substituted Coumarin Derivatives and Other Potential Antimycobacterial Agents

INTRODUCTION: The growing burden of drug-resistant mycobacterial infections demands novel therapeutic agents. One strategy for discovering new tuberculosis (TB) drugs is to target essential proteins within validated biosynthetic pathways. FadD32 is a key enzyme in mycolic acid synthesis and is critical for the viability of Mycobacterium tuberculosis (Mtb). Accordingly, identifying potent FadD32 inhibitors represents a promising approach that may help circumvent resistance to existing TB drugs such as isoniazid. METHODS: This study employed structure-based drug design using molecular docking to evaluate the binding potential of 7-substituted coumarin derivatives and compounds from the Maybridge database against FadD32. Docking was performed using Hybrid 4.0 software. Top-scoring ligands were screened for antimycobacterial activity against Mycobacterium smegmatis mc²155 using the Alamar Blue assay. RESULTS: All 7-substituted coumarin derivatives exhibited better docking scores than the native ligand of FadD32. Additionally, 14 Maybridge compounds, including diverse scaffolds, also showed favorable docking results. Among them, HTS08202 (a benzimidazole derivative) demonstrated significant activity, inhibiting M. smegmatis mc2155 by 94.12% (±2.34%) and 94.82% (±1.73%) at 50 μM and 25 μM, respectively. CP15, a coumarin-based compound, achieved 82.38% (±3.18%) inhibition at 50 μM. Cytotoxicity assessment revealed that HTS08202 was not toxic at 25 μM, its active concentration. DISCUSSION: The findings highlight the potential of both benzimidazole and coumarin-based derivatives as promising leads for antimycobacterial drug development. The favorable docking scores and biological activity suggest that FadD32 inhibition may be a viable strategy to overcome resistance mechanisms in TB. HTS08202 stands out for its higher inhibition and lower cytotoxicity, and requires further optimization and in vivo evaluation. CONCLUSION: The identified compounds, especially HTS08202 merit further investigation as potential antimycobacterial agents.