Synthesis and structure–activity relationship of 2-thiopyrimidine-4-one analogs as antimicrobial and anticancer agents

Considering that some thiopyrimidines were previously reported as potential therapeutics, the present study achieved novel analogs of bioactive 2-substituted thiopyrimidines-4-(3H)-ones via base catalyzed alkylation reaction of 2-thiouracil using alkyl and aralkyl bromides. The title compounds were 2-(1-butylthio)pyrimidine-4(3H)-one (5a), 2-(2-butylthio)pyrimidine-4(3H)-one (5b), 2-(cyclohexylmethylthio)pyrimidine-4(3H)-one (5c), 2-(benzylthio)pyrimidine-4(3H)-one (5d) and 2-(1-adamantylthio)pyrimidine-4(3H)-one (5e). Bioactivity tests revealed that thiopyrimidines 5a, 5c, 5d and 5e exhibited antimicrobial activity. The thiopyrimidine-4-one (5c) showed complete inhibition against Streptococcus pyogenes and Branhamella catarrhalis as well as antifungal action against Candida albicans. Significantly, the 1-adamantylthiopyrimidine (5e) was shown to be the most potent cytotoxic compound against multidrug-resistant small cell lung cancer (H69AR). Their structure–activity relationships were discussed.

Graphical abstract2-Thiopyrimidine-4-ones (5a–e) were synthesized to yield antimicrobial and potent cytotoxic activities. Their structure–activity relationships were described.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► Novel analogs of 2-thiopyrimidine-4-ones were synthesized via S-alkylation of 2-thiouracil. ► The S-alkylated (R) pyrimidine analogs inhibited growth of B. catarrhalis where R = CH2C6H11 group. ► When R = 1-adamantyl (1-Adm) moiety, it exhibited the most potent cytotoxic activity against H69AR. ► The SAR showed the important of alkylated groups for significant bioactivity of 1-Adm and CH2C6H11.