The present article describes the synthesis,
in vitro urease inhibition and
in silico molecular docking studies of a novel series of bi-heterocyclic bi-amides. The synthesis of title compounds was initiated by benzoylation, with benzoyl chloride (
1), of the key starter ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (
2) in weak basic aqueous medium followed by hydrazide formation,
4, and cyclization with CS
2 to reach the parent bi-heterocyclic nucleophile,
N-{4-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-thiazol-2-yl}benzamide (
5). Various electrophiles,
8a–l, were synthesized by a two-step process and these were finally coupled with
5 to yield the targeted bi-heterocyclic bi-amide molecules,
9a–l. The structures of the newly synthesized products were corroborated by IR,
1H NMR,
13C NMR, EI-MS and elemental analysis. The
in vitro screening of these molecules against urease explored that most of the compounds exhibit potent inhibitory potential against this enzyme. The compound
9j, with IC
50 value of 2.58?±?0.02?µM, exhibited most promising inhibitory activity among the series, relative to standard thiourea having IC
50 value of 21.11?±?0.12?µM.
In silico studies fully augmented the experimental enzyme inhibition results. Chemo-informatics analysis showed that synthesized compounds (
9a–l) mostly obeyed the Lipinski's rule. Molecular docking study suggested that ligand
9j exhibited good binding energy value (?7.10?kcal/mol) and binds within the active region of target protein. So, on the basis of present investigation, it was inferred that
9j may serve as a novel scaffold for designing more potent urease inhibitors.
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