Abstract
During the course of our research into new anti-malaria drugs, Plasmodium falciparum thymidylate kinase (PfTMK) has emerged as an important drug target because of its unique substrate specificity. Compared with human thymidylate kinase (HsTMK), PfTMK shows broader substrate specificity, which includes both purine and pyrimidine nucleotides. PfTMK accepts both 2′-deoxyguanosine monophosphate (dGMP) and thymidine monosphosphate (TMP) as substrates. We have evaluated the inhibitory activity of seven carbocyclic thymidine analogs and report the first structure‒activity relationship for these inhibitors against PfTMK. The 2′,3′ dideoxycarbocyclic derivative of thymidine showed the most potent inhibition of the enzyme. The KidTMP and KidGMP values were 20 and 7μM respectively. Thus, further modifications of carbocyclic thymidine analogs represent a good strategy for developing more powerful thymidylate kinase inhibitors.
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► We designed a series of carbocyclic nucleoside analogs. ► We established the first structure–activity relationship. ► Several carbocyclic thymidine analogs were good inhibitors. ► The Ki values against PfTMK was in the low micromolar range.