Antimycobacterial Agents. 1. Thio Analogues of Purine

Abstract

Thio analogues of purine, pyridine, and pyrimidine were prepared based on the initial activity screening of several analogues of these heterocycles against Mycobacterium tuberculosis (Mtb). Certain 6-thio-substituted purine analogues described herein showed moderate to good inhibitory activity. In particular, two purine analogues 9-(ethylcarboxymethyl)-6-(decylthio)-9H-purine (20) and 9-(ethylcarboxymethyl)-6-(dodecylthio)-9H-purine (21) exhibited MIC values of 1.56 and 0.78 microg/mL respectively against the Mtb H(37)Rv strain. N(9)-Substitution apparently enhances the antimycobacterial activity in the purine series described herein.

New Small-Molecule Synthetic Antimycobacterials

“…Several 9-benzylpurines have been found to exhibit very good inhibitory activity against M. tuberculosis ( Table 2, compound 26) (46,74). The MIC of the leading compound was 0.78 g/ml, with moderate toxicity levels against Vero cell lines (SI ϭ 10.6).…”

Recent Efforts for the Development of Antitubercular Drug Containing Diazine Ring

“…Among all, 2-chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-purine (48) exhibited best potency of MIC 0.39 μg/mL and also low toxicity against mammalian cells and activity inside macrophages [70,71]. Purine derivatives 9-(ethylcarboxymethyl)-6-(dodecylthio)-9H-purine (49) were showed MIC value of 0.78 μg/mL [72]. In the analogues of agelasine E (50), one derivative (51) showed promising activity with MIC of 1.56 μg/mL against Mtb H37Rv [70,71].…”

New drugs and vaccines for drug-resistantMycobacterium tuberculosisinfections

“…Recently, the screening of novel compounds has highlighted modified purines as potential antimycobacterial drugs [126][127][128][129]. Screening of a library of 6-substituted and 2,6-di-substituted 9-benzyl-purines revealed several compounds with encouraging activity against M. tuberculosis, with a general trend suggesting that 6-substituted varieties were more effective than their disubstituted counterparts, although chlorination at the 2 position did tend to increase activity [126].…”

“…Screening of another library of 6-thiopurines incorporating 6-thioaryl/alkyl-urines, 2-thioaryl/alkyl-pyrimidines and 2-and 4-thioaryl/alkyl-pyridines identified highly active compounds 9-(ethylcarboxymethyl)-6-(decylthio)-9H-purine and 9-(ethylcarboxymethyl)-6-(dodecylthio)-9H-purine with MICs of 1.56 and 0.78 µg/ml, respectively, against M. tuberculosis H37Rv with the former showing good activity against the Erdman strain in bone marrow macrophages [129]. Together, these various studies demonstrate that further development of these purine derivatives may generate interesting novel anti-TB agents.…”