title: Design, synthesis, and biological evaluation of new cinnamic derivatives as antituberculosis agents.
abstract: 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 (H(37)Rv). 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.
authors.affiliation: Université de Toulouse, UPS, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France.
authors.forename: Prithwiraj
authors.initials: P
authors.lastname: De
authors.forename: Georges
authors.initials: G
authors.lastname: Koumba Yoya
authors.forename: Patricia
authors.initials: P
authors.lastname: Constant
authors.forename: Florence
authors.initials: F
authors.lastname: Bedos-Belval
authors.forename: Hubert
authors.initials: H
authors.lastname: Duran
authors.forename: Nathalie
authors.initials: N
authors.lastname: Saffon
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.forename: Michel
authors.initials: M
authors.lastname: Baltas
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects; D009171:Mycolic Acids / Q000032:analysis; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C558528:3-(4-(3-methylbut-2-enyloxy)styryl)-(1,2,4)triazolo(3,4-a)phthalazine; D000577:Amides; D000995:Antitubercular Agents; D002934:Cinnamates; D006834:Hydrazines; D009171:Mycolic Acids; D010793:Phthalazines; D014230:Triazoles; D007538:Isoniazid