6315-47-5

Abstract: In the present research work, a new series of N-(substituted-phenyl)-3-(4-phenyl-1-piperazinyl)propanamides were synthesized. The synthesis was initiated by the coupling of different aromatic amines with 3-bromopropanoyl chloride in aqueous basic medium, to synthesize different electrophiles with good yields. These electrophiles were further reacted with 1-phenylpiperazine to yield the desired compounds, N-(substituted-phenyl)-3-(4-phenyl-1-piperazinyl)propanamides as depicted in scheme 1. The structural confirmation of all the synthesized compounds was corroborated by IR, 1H NMR, 13C NMR, HMBC and CHN analysis data. The in vitro inhibitory potential of these propanamides was evaluated against alkaline phosphatase enzyme and it was explored that all these molecules exhibit potent inhibition relative to the standard used. The Kinetics mechanism analyzed by Lineweaver-Burk plots which exposed that N-(4-ethylphenyl)-3-(4-phenyl-1-piperazinyl)propanamide inhibited this enzyme competitively by forming an enzyme-inhibitor complex. Moreover, these compounds were studied for cytotoxic behaviour by hemolytic activity, whereby it was avowed that nearly all these propanamides disclosed low cytotoxicity. In addition, kinetic analysis were also carried out to understand the mode of inhibition for these compounds. The in silico investigation of these compounds was also in agreement with the in vitro results. So, it was envisaged that these derivatives might lead to further research gateways for obtaining better and safe as nontoxic medicinal scaffolds for dealing with the alkaline phasphatase related ailments such as bone diseases, diabetes, prostatic cancer and liver dysfunction.

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 CS2 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 IC50 value of 2.58 ± 0.02 μM, exhibited most promising inhibitory activity among the series, relative to standard thiourea having IC50 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.