Design, synthesis, characterization, and docking studies of hiherto unkown chlorinated thiazolidine, thiophene, and 2-iminochromene derivatives as protein-like protease inhibitors

Abstract

The present work details the synthesis of several intriguing nitrogenous heterocycles utilizing a cyano-N-aryl-acetamide-reagent, notably chlorinated thiazolidine, thiophene and 2-iminochromene derivatives. Thus, the precursor 2-cyano-N-(2,4-dichlorophenyl) acetamide 1 underwent the reaction with phenyl isothiocyanate in DMF/KOH to afford the intermediate salt 3, which reacted in situ with several α-halogenated reagents 4a-c like ethylchloroacetate,α-bromoethylpropionate and α-bromo ethyl butaneoate and afforded the corresponding 4-thiazolidinnone derivatives (6a–c, yield%; 67–85), thiophene derivatives (11;yield 80%) and (15, yield 77%) obtained from the reaction of 3 with α- chloroacetyl acetone 9 and ethyl 2-chloro-3-oxobutanoate 12.Novel series of different 4-thiazolidinones(16a–e; yield%; 65–84) were obtained via condensation of 6a with different aldehydes. Finally, the reaction of compound 1 with different bifunctional reagents, such as salicylaldehyde derivatives and 2-hydroxynaphthaldehyde, in ethanol furnished the iminochromenes (17a,b; yield %77,80) and (18; yield 85%). In addition, molecular docking studies of the prepared molecules were carried out against papain-like protease (PLpro) to identify novel promising inhibitors of Coronavirus Disease COVID-19. The binding affinity of the best docked compounds 16c and 16a toward the target enzyme was − 9.6 and − 8.9 kcal/mole, respectively. In silico-docking-Studies indicate, that compounds 16c and 16a have the potential as antiviral against COVID-19.

Graphical abstract