Abstract
Background: One of the successful approaches for rational design of bioactive compounds is the bioisosterism strategy. Thus, the bioisosteric relation of thieno[2,3-d]pyrimidin-4- ones with quinazolines, cytosine and uracil resulted in the generation of compounds with variety of biological properties including antiparasitic activity. In contrast to mammals, all parasites are unable to synthesize purines de novo and rely instead on the Purine Salvage Pathway (PSP) to obtain purines, which are essential for their survival. Having in view the above mentioned facts we designed and synthesized some thieno[2,3-d]pyrimidines as bioisosters in order to evaluate their antitrichinellosis efficacy.
Methods: The target compounds were synthesized by one-pot cyclocondensation reaction passing dry hydrogen chloride gas through a solution of 2-aminothiophene-carboxylate and a series of alkyl respectively aryl nitriles as precursors.
The parasitological screening in vitro was carried out by using encapsulated infective larvae of Trichinella spiralis, 100 speciments per 1 mL physiological solution, released in advance from the muscle capsules by digestion with acid pepsin solution.
Results: Fourteen 2-substituted-thieno[2,3-d]pyrimidin-4-ones were synthesized and their structure was identified. The data obtained by the antitrichinellosis screening showed that compounds 2, 8 and 15 exhibit higher activity than the reference drugs albendazole and ivermectin at concentrations of 0.37, 0.35 and 0.48 µM resp. 0.92, 0.88 and 1.2 µM after 24-hour incubation of the samples. The highest efficacy at both incubations was revealed by 2-benzyl-5,6,7,8- tetrahydrothieno[2,3-d]pyrimidin-4(3H)-one 2 - 97.94% and 100%, respectively. Compound 15 demonstrated 97.5% antiparasitic activity after 48h at concentration of 250 μg/ml. The theoretically calculated intestinal absorption (%ABS) of the tested thieno[2,3-d]pyrimidines displayed higher values than that of albendazole. The structure-activity relationship (SAR) data of the tested compounds 2, 4-8 and 15 complies with the Lipinski's rule. It was assumed that the low molecular volume (Vol.) and logP of compound 15 led to enhancement of the compound activity by increasing the penetration through the ion channels of the parasitic cells as it was observed in some albendazole derivatives.
Conclusion: The tested thienopyrimidin-4-ones possess higher anthelminthic effect than albendazole against Trichinella spiralis. Compounds 2, 4-8 and 15 demonstrated higher absorption %ABS than albendazole. According to the SAR analysis, the partition coefficient (logP) is essential for parasite drug penetration due to diffusion through the cell membrane.
Keywords: Thieno[2, 3-d]pyrimidines, bioisosterism, SAR, antiparasitic activity, Trichinella spiralis, Lipinski's rule.
Graphical Abstract
25
2
1
1