Recent advances in anti-infective drug discovery · 2026
Rational Design, Synthesis, Molecular Docking, and Evaluation of Thioridazine-modified Tetrahydrocarbazole Derivatives as Antitubercular Agents.
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Sellamuthu Satheeshkumar, Thangaraj Boopathi, Kumar Dileep
Аннотация
INTRODUCTION: Although thioridazine has shown antitubercular potential, its neuroleptic effects limit its safe repurposing as an anti-TB agent. This study aimed to develop thioridazine-based drug candidates with reduced ability to cross the BBB while retaining antitubercular efficacy.
METHODS: The synthesized tetrahydrocarbazole derivatives were evaluated for antitubercular and antibacterial activity using the Alamar Blue and disc diffusion assays, respectively, alongside BBB permeability (PAMPA) and cytotoxicity (MTT, VERO cells) assessments.
RESULTS: Compounds 10e, 11e, and 13e exhibited the strongest activity against the M. tuberculosis H37Rv with an MIC of 3.13 μg/mL. The activity was associated with meta- and para-substituted nitro and carboxylic groups, whereas ortho substitution and other substituents reduced potency. The activity of these compounds was comparable to that of pyrazinamide but lower than that of isoniazid and ethambutol. The compounds showed greater antibacterial activity against S. aureus than E. coli. The PAMPA-BBB permeability study showed reduced permeability compared with thioridazine (2.1-2.6 × 10⁻⁸ m/s). Cytotoxicity study demonstrated high selectivity towards M. tuberculosis over VERO cells (SI > 44). Docking analysis suggested a favorable interaction with CmaA2.
DISCUSSION: The electron-withdrawing substituents at meta- and para-positions enhanced antitubercular potency, whereas ortho substitution was found unfavorable. Although MIC values approached those of pyrazinamide, therapeutic equivalence cannot be assumed due to mechanistic differences. Reduced BBB permeability suggests improved CNS safety over thioridazine, though limited CNS exposure may still occur. High selectivity and CmaA2 binding support these compounds as promising leads, warranting further validation.
CONCLUSION: Thioridazine-derived tetrahydrocarbazoles showed antitubercular activity against M. tuberculosis H37Rv with MIC values comparable to pyrazinamide. Further, the lead compounds demonstrated reduced BBB permeability and favourable selectivity towards M. tuberculosis over VERO cells. The docking study provided supportive, nonmechanistic insights into possible CmaA2 interaction. These findings warrant further in vivo evaluation and mechanistic investigation.
METHODS: The synthesized tetrahydrocarbazole derivatives were evaluated for antitubercular and antibacterial activity using the Alamar Blue and disc diffusion assays, respectively, alongside BBB permeability (PAMPA) and cytotoxicity (MTT, VERO cells) assessments.
RESULTS: Compounds 10e, 11e, and 13e exhibited the strongest activity against the M. tuberculosis H37Rv with an MIC of 3.13 μg/mL. The activity was associated with meta- and para-substituted nitro and carboxylic groups, whereas ortho substitution and other substituents reduced potency. The activity of these compounds was comparable to that of pyrazinamide but lower than that of isoniazid and ethambutol. The compounds showed greater antibacterial activity against S. aureus than E. coli. The PAMPA-BBB permeability study showed reduced permeability compared with thioridazine (2.1-2.6 × 10⁻⁸ m/s). Cytotoxicity study demonstrated high selectivity towards M. tuberculosis over VERO cells (SI > 44). Docking analysis suggested a favorable interaction with CmaA2.
DISCUSSION: The electron-withdrawing substituents at meta- and para-positions enhanced antitubercular potency, whereas ortho substitution was found unfavorable. Although MIC values approached those of pyrazinamide, therapeutic equivalence cannot be assumed due to mechanistic differences. Reduced BBB permeability suggests improved CNS safety over thioridazine, though limited CNS exposure may still occur. High selectivity and CmaA2 binding support these compounds as promising leads, warranting further validation.
CONCLUSION: Thioridazine-derived tetrahydrocarbazoles showed antitubercular activity against M. tuberculosis H37Rv with MIC values comparable to pyrazinamide. Further, the lead compounds demonstrated reduced BBB permeability and favourable selectivity towards M. tuberculosis over VERO cells. The docking study provided supportive, nonmechanistic insights into possible CmaA2 interaction. These findings warrant further in vivo evaluation and mechanistic investigation.