Synthesis and Antiplatelet and Anticoagulant Activity of Thietane-Containing 2-(5-Bromo-2,4-Dihydro-3-Oxo-1,2,4-Triazolyl-4)Acetate Salts

Abstract

Sulfone II was synthesized via oxidation of ethyl 2-[5-bromo-2,4-dihydro-3-oxo-2-(thietanyl-3)-1,2,4-triazolyl- 4]acetate ( I ) by H 2 O 2 . Hydrolysis of esters I and II synthesized 2-[5-bromo-2,4-dihydro- 3-oxo-2-(thietanyl-3)-1,2,4-triazolyl-4]- and 2-[5-bromo-2,4-dihydro-3-oxo-2-(1,1-dioxothietanyl-3)-1,2,4- triazolyl-4]acetic acids III and IV , respectively.Water-soluble salts V and VI were prepared by reacting acids III and IV with alkali-metal hydroxides and amines. The structures of the synthesized compounds were confirmed IR and NMR spectroscopic data. The antiplatelet and anticoagulant activity of the synthesized compounds was studied in vitro based on predictions of the PASS computer program. Compounds III and VIb , which showed the absence of predicted toxic risks and were superior to the reference drug in the collagen-induced aggregation test, had the most pronounced antiplatelet activity (comparable to that of acetylsalicylic acid) in the ADP-induced aggregation test. The anticoagulant activity of the compounds was significantly inferior to that of heparin sodium. All synthesized compounds satisfied Lipinski’s rule-of-5.

Novel Substituted Azoloazines with Anticoagulant Activity

“…To find out the "structure-activity" relations for substituted azolo[1,5-а]pyrimidines, we synthesized compounds bearing aryl, hetaryl or the nitro substituents in the pyrimidine ring. [6]. Hydrogenated analogues of azolo[1,5-a]pyrimidines, as well as their salts with guanidine, which are an important fragment of the known anticoagulants, have been obtained.…”

“…These compounds can be regarded as structural analogues of purine bases. Indeed, these compounds can act as antimetabolites or enzyme inhibitors, and are known to have a wide spectrum of biological activity [5,6] (Figure 1). In particular, they exhibit antiviral activity, and some compounds of this series are characterized by activity against the main 3CLpro-2 protease of the coronavirus, which is involved in the maturation and replication of the SARS-CoV-2 virus [7].…”