Discovery and Evaluation of Novel Dicarbonyl Amide Dihydropyridines asAntitubercular Agents

Introduction: Treatment of tuberculosis remains restricted to a limited number of drugs, and resistance to these agents continues to increase. The number of promising new drug candidates is currently low. Isoniazid, one of the first-line agents, has even been considered for replacement by moxifloxacin in initial therapy. Consequently, novel antimycobacterial compounds are urgently needed to expand the small repertoire of effective treatments for tuberculosis. Methods: We synthesized a series of novel dicarbonyl amide compounds built on a 1,4- dihydropyridine scaffold stabilized against oxidation through nitrogen substitution. Their antimycobacterial activity was evaluated to establish a new class of compounds related to isoniazid, which is a pyridine-based molecule with a hydrazide structure Results: Two dihydrazide compound series featuring varied aromatic substituents at the nitrogen atom and at the 4-position of the dihydropyridine ring showed limited activity. In contrast, the dicarbonyl amide series containing a monoalkyl residue demonstrated higher activity, particularly derivatives with a benzylamide substituent. Discussion: Compounds carrying a methoxy group at the 4-position of the 4-phenyl substituent, such as 6c, or on the phenyl ring attached to the nitrogen atom, as in 6e, showed the strongest activities. These effects were further surpassed by 7c, which contains an ethylamide residue Conclusion: We identified novel dicarbonyl amide compounds as promising antimycobacterial agents, with methoxy-substituted derivatives exhibiting superior activity. These compounds represent a new class of candidates for combating drug-resistant tuberculosis and may substantially expand the future pool of therapeutic agents.