Synthesis, evaluation of antimicrobial activity and molecular docking of new N-1,3-thiazol-2-ylacetamides of condensed pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines.

Abstract

BACKGROUND From the literature it is known that many derivatives of fused thienopyrimidines and furopyrimidines possess broad spectrum of biological activity. OBJECTIVES The current studies describe the synthesis and evaluation of antimicrobial activity of some new N-1,3-thiazol-2- ylacetamides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines. METHOD By cyclocondensation of ethyl 1-aminofuro(thieno)[2,3-b]pyridine-2-carboxylates 1with Formamide were converted to the pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidin-7(8)-ones 2.Alkylation of compound 2 with 2-chloro-N-1,3-thiazol-2- ylacetamide led to the aimed N-1,3-thiazol-2-ylaceta-mides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 3. Starting from compound 2 the relevant S-alkylated derivatives of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 6 were also synthesized. RESULTS All compounds showed antibacterial activity to non-resistant strains. Compounds 3a-3m showed antibacterial activity with MIC/MBC at 0.08-2.31 mg/mL/0.11-3.75 mg/mL .Two the most active compounds 3j and 6b appeared to be more active than MRSA than reference drugs. These compounds exhibitedalso better effect to biofilm formation than reference drugs. Half of the tested compounds appeared to be equipotent/more potent than ketoconazole and more potent than bifonazole. A docking analysis has furnished useful information about the interactions occurring between the tested compounds and the different enzymes. CONCLUSION Gram-negative and Gram-positive bacteria and fungi showed different response towards tested compounds, indicating that different substituents may lead to different modes of action or that the metabolism of some bacteria/fungi was better able to overcome the effect of the compounds or adapt to it.