Synthesis and evaluation of novel 1, 2, 4-substituted triazoles for urease and anti-proliferative activity.

Ali, Saima; Siddiqui, Sabahat Zahra; Abbasi, Muhammad Athar; Aziz-ur-Rehman; Shah, Syed Adnan Ali; Khan, Khalid Mohammed; Saleem, Rahman Shah Zaib; Manzoor, Safia; Ashraf, Muhammad; Zia-ur-Rehman

1,2,4-triazoles are a major group of heterocyclic compounds. In the current work, a concise library of such triazoles synthesized through a multistep protocol. The synthesis involved hydrazinolysis of ethyl-2-(p-Cl-phenoxy) acetate followed by reflux with phenyl isothiocyanate to yield the intermediate 2-[2-(p-Cl-phenoxy)acetyl)-N-phenylhydrazinecarbothioamide. This intermediate was then cyclized to form 5-[p-(Cl-phenoxy)-methyl]-4-phenyl-4H-1,2,4-triazole-3-thiol (the parent moiety) at alkaline pH. In parallel, 3-bromopropionyl bromide was reacted with a series of phenylamines to yield N-(substituted-phenyl)bromopropanamides. In the final step, N-substitution of 5-[p-(Cl-phenoxy)-methyl]-4-phenyl-4H-1,2,4-triazole-3-thiol was carried out with N-(substituted-phenyl)bromopropanamides to give desired library of 3-[5-[(p-Cl-phenoxy)-methyl]-4-phenyl-4H-1,2,4-triazole-3-ylthio]-N-(substituted-phenyl) propanamides (8a-l). The prepared moieties were identified via IR, NMR, & EIMS and evaluated for urease and antiproliferative activities. 3-[5-[(p-Cl-phenoxy)-methyl]-4-phenyl-4H-1,2,4-triazole-3-ylthio]-N-(3-methylphenyl) propanamide 8k, was found to be most prominent hit as urease inhibitor (IC50= 42.57± 0.13 µM) using thiourea as standard (IC50= 21.25±0.15µM). The interaction of 8k with urease were studied using docking studies. Antiproliferative activity results showed 8k as promising candidates and rest of the synthesized derivatives were found to be moderately anti-proliferative. Molecular docking results also displayed 8k, 8h, and 8c as potential hits for further study.

UREASE; TRIAZOLES; HETEROCYCLIC compounds; MOLECULAR docking; ISOTHIOCYANATES; ANILINE; THIOUREA

Pakistan Journal of Pharmaceutical Sciences, 2022, Vol 35, p209

1011-601X

Academic Journal

10.36721/PJPS.2022.35.1.SUP.209-217.1