Synthesis of novel 2,4-bis(substituted phenoxy)-6-(phenylthio) pyrimidine analogs and their antimicrobial activities

Abstract

Background/aimsPyrimidines have a long and distinguished history extending from the days of their discovery as important constituents of nucleic acids to their current use in medicinal chemistry. As a part of project devoted to the development of pyrimidine analogs as antimicrobial agents we have focused our attention on synthesis of C5/C6 substituted pyrimidine derivatives, specifically C6 substituted pyrimidine analogs which have emerged as potent molecule in recent years. Methods2,4-Bis(substituted phenoxy)-6-(phenylthio)pyrimidines were prepared in five steps starting from barbituric acid. Initial reaction of barbituric acid (1) with POCl3 in presence of N,N-dimethylaniline under reflux furnished 2,4,6-trichloropyrimidine (2), which on hydrolysis with aq. NaOH under reflux yielded 6-chlorouracil (3). 6-Chlorourail on treatment with thiophenol in dry pyridine generated 6-phenylthiouracil (4), chlorination of 4 using excess POCl3 under reflux afforded the key synthon 2,4-dichloro-6-(phenylthio)pyrimidine (5). Aromatic nucleophillic substitution reaction of 5 with oxygen nucleophiles like sodium phenoxides provided the desired targeted compounds 6a–g in 62–86% yield. Structural assignments of the synthesized compounds were based on their IR, 1H NMR, mass and analytical data. The antimicrobial evaluation of newly synthesized compounds was carried out by cup–plate method. ResultsThe investigation of antimicrobial screening reveals that the compounds 5, 6b, 6c and 6f showed good activity against fungal strains comparable to the standard drug Flucanazole. Remaining compounds exhibited moderate activity against bacterial and fungal strains compared to standard drug. ConclusionWe have developed a facile methodology which avoids the use of moisture sensitive reagents like organolithiums, diphenyl disulphide, etc. The C6 substituted pyrimidine analogs can be considered for further studies as potent antifungal agents.