Design, Synthesis, and Biological Evaluation of New Cinnamic Derivatives as Antituberculosis Agents

Prithwiraj De (1) , Georges Koumba Yoya (1) , Patricia Constant (2) , Florence Bedos-Belval (1) , Hubert Duran (1) , Nathalie Saffon (3) , Mamadou Daffé (2) , Michel Baltas (1)

1 SPCMIB - Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique
2 IPBS - Institut de pharmacologie et de biologie structurale
3 SFTCM - Structure Fédérative Toulousaine en Chimie Moléculaire

Tuberculosis, HIV coinfection with TB, emergence of multidrug-resistant TB, and extensively drug-resistant TB are the major causes of death from infectious diseases worldwide. Because no new drug has been introduced in the last several decades, new classes of molecules as anti-TB drugs are urgently needed. Herein, we report the synthesis and structure−activity relationships of a series of thioester, amide, hydrazide, and triazolophthalazine derivatives of 4-alkoxy cinnamic acid. Many compounds exhibited submicromolar minimum inhibitory concentrations against Mycobacterium tuberculosis strain (H37Rv). Interestingly, compound 13e, a 4-isopentenyloxycinnamyl triazolophthalazine derivative, was found to be 100−1800 times more active than isoniazid (INH) when tested for its ability to inhibit the growth of INH-resistant M. tuberculosis strains. The results also revealed that 13e does not interfere with mycolic acid biosynthesis, thereby pointing to a different mode of action and representing an attractive lead compound for the development of new anti-TB agents.

Mots clés: Reaction products; Bacteria; Biosynthesis; Alkyls; Toxicity

Domaines: Sciences pharmaceutiques

Prithwiraj De, Georges Koumba Yoya, Patricia Constant, Florence Bedos-Belval, Hubert Duran, et al.. Design, Synthesis, and Biological Evaluation of New Cinnamic Derivatives as Antituberculosis Agents. Journal of Medicinal Chemistry, 2011, 54 (5), pp.1449-1461. ⟨10.1021/jm101510d⟩. ⟨hal-03102544⟩