Synthesis of pyrazinamide analogues and their antitubercular bioactivity
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Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02626-0
ORIGINAL RESEARCH
Synthesis of pyrazinamide analogues and their antitubercular bioactivity First A. Wati1 Prisna U. Adyarini1 Sri Fatmawati1 Mardi Santoso ●
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Received: 18 June 2020 / Accepted: 29 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The Yamaguchi reaction is widely and generally applied to synthesize esters and lactones. It involves 2,4,6-trichlorobenzoyl chloride as the Yamaguchi reagent, 4-dimethylaminopyridine, and triethylamine. Pyrazinamide is a crucial first-line drug for tuberculosis treatment, therefore their analogues are interesting in organic synthesis. In general, the synthesis pyrazinamide analogues involve reaction of pyrazine-2-carboxylic acids with thionyl chloride to yield the corresponding acyl chlorides, which on treatment with amines gave pyrazine-2-carboxamides. However, thionyl chloride is listed under the Chemical Weapons Convention and releases toxic sulfur oxide when react with carboxylic acid. We successfully synthesized series of pyrazinamide analogues using the Yamaguchi reaction. The synthesis involved reaction of pyrazine-2-carboxylic acid with various aliphatic and aromatic amines in the presence of Yamaguchi reagent and 4-dimethylaminopyridine. The yield of the pyrazine-2-carboxamides and the reaction time depended on the type of the amine (aliphatic vs aromatic), substitution pattern, and number of substituents on the aromatic amines. N-(4-chlorophenyl)pyrazine-2-carboxamides can be prepared by this method in 81% yield; N-(2-ethylhexyl)pyrazine-2-carboxamide and N-(4-fluorobenzyl)pyrazine-2-carboxamide showed the best activity against Mycobacterium tuberculosis H37Rv (24 h [7, 8]. Another synthetic method involves decarboxylation reaction of 2,3pyrazinedicarboxylic anhydride with anilines and amines in refluxing toluene. However, secondary amines give pyrazine2,3-dicarboximides as a by-product [9]. Cerium oxide (CeO2) is also used to catalyze pyrazine-2-carboxamide synthesis, but needs high temperature of 160 °C [10, 11]. Therefore, there is a need to develop environmentally friendly, mild, and effective method to synthesize PZA series. Yamaguchi reaction is commonly utilized to prepare esters and thioesters using 2,4,6-trichlorobenzoyl chloride. The reaction is carried out by two steps: anhydride formation followed by reaction with alcohols or thiols in the presence of 4-dimethylaminopyridine (DMAP). The reaction is considerably mild, fast, and gives good yields [12– 14]. To our knowledge, the reaction has not been well explored for the synthesis of amides in general [15] and certainly not for the synthesis of pyrazine-2-carboxamides. Herein, we developed one-pot Yamaguchi reaction and synthesized a series of PZA analogues. Furthermore, the antimycobacterial activity of these compounds was studied.
General procedure for synthesis of PZA analogues (3a–t) To the solution of pyrazine-2-carboxylic acid (1.05 eq) in tetr
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