Efficient L-Proline catalyzed synthesis of some new (4-substituted-phenyl)-1,5-dihydro-2H-pyrimido[4,5-d][1,3]thiazolo[3,2a]-pyrimidine-2,4(3H)-diones bearing thiazolopyrimidine derivatives and evaluation of their pharmacological activities

Abstract

In the present study, a simple and efficient protocol has been developed to synthesize a series of new (4-substituted-phenyl)-1,5-dihydro-2H-pyrimido[4,5-d][1,3]thiazolo[3,2a]-pyrimidine-2,4(3H)-dione derivatives (4a-g) through L-proline-catalyzed reaction of 2-amino-4-(4-substituted-phenyl)thiazole (1), substituted benzaldehyde (2), and barbituric/thiobarbituric acid (3) at a refluxed temperature in aqueous ethanol under mild and metal-free conditions. The obtained compounds were evaluated for in vitro cytotoxicity and anti-inflammatory effects. The in silico docking studies provided the probable interactions of synthesized compounds with P38 MAP kinase and MMP-9 proteins. The structures of all the synthesized compounds were confirmed using analytical and spectroscopic techniques. The in vitro cytotoxicity studies revealed the potential cytotoxic effects of the compounds 4f and 4g. The anti-inflammatory studies suggested the prominent anti-inflammatory effects of the compounds 4a and 4g. The SAR studies showed the importance of electron-withdrawing groups in enhancing the potency among the tested compounds. The results of in silico studies supported our findings from in vitro analysis in terms of drug-likeness of the synthesized compounds and their effective interactions with P38 MAP kinase and MMP-9 proteins envisaging their use as prominent therapeutic agents.