Inhibition Profiling Of Urease And Carbonic Anhydrase Ii By High-Throughput Screening And Molecular Docking Studies Of Structurally Diverse Organic Compounds

Background: Structurally diverse organic compounds and available drugs were screened against urease and carbonic anhydrase II in a formulation acceptable for high-throughput screening. Objective: The study was conducted to find out potential inhibitors of urease and carbonic anhydrase II.Methods: Quantification of the possible HITs was carried out by determining their IC50 values.Results: The results of several screened compounds, including derivatives of oxadiazole, coumarins, chromane-2, 4-diones and metal complexes of cysteine-omeprazole showed promising inhibitory activities with IC50 ranging from 47 mu M to 412 mu M against the urease. The interactions of active compounds with active sites of enzymes were investigated through molecular docking studies which revealed that (R)-1-(4-amino-4-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl) butyl) guanidine possessing IC50 of 47 mu M interacts with one of the nickel metal atoms of urease besides further interactions as predictable hydrogen bonds with KCX490, Asp633, His492, His407 and His409 along with Ala440 and 636. Bi-ligand metal complexes of 4-aminoantipyrine based Schiff bases showed activation of urease with AC(50) ranging from 68 mu M to 112 mu M. Almost 21 compounds with varying functional groups including pyrimidines, oxadiazoles, imidazoles, hydrazides and tin based compounds were active carbonic anhydrase II inhibitors presenting 98 mu M to 390 mu M IC50 values. Several N-substituted sulfonamide derivatives were inactive against carbonic anhydrase II.Conclusion: Among all the screened compounds, the highly active inhibitor of carbonic anhydrase II was (4-(3-hydroxyphenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl) methanone with IC50 of 98.0 mu M. This particular compound showed metallic interaction with Zn ion of carbonic anhydrase II through the hydroxyl group of the phenyl ring.