Synthesis, Spectral Evaluation and in Silico Studies of S-Aralkylated 5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols: As suitable Alzheimer's disease drug candidates.

Arfan, Muhammad; Siddiqui, Sabahat Zahra; Abbasi, Muhammad Athar; Aziz-ur-Rehman; Shah, Syed Adnan Ali; Ashraf, Muhammad; Khan, Khalid Mohammed; Saleem, Rahman Shah Zaib; Zaib, Amna Shah

Summary: Our efforts lay emphasis on synthesis of S-aralkylated 5-(4-OMeC6H5)-4-phenyl-4H-1,2,4-triazol-3-thiols like pharmacologically active candidates to counter neurodegenerative disorder; Alzheimer's disease. A synthetic strategy was instigated by esterifying 4-methoxybenzoic acid through Fisher esterification's methodology. Hydrazinolysis of corresponding ester was performed under reflux with methanolic hydrated hydrazine to afford 4-methoxybenzohydrazide (I) which refluxing with phenyl isothiocyanate (II) in MeOH to yield a reactive intermediate (III). The later underwent base-catalyzed intermolecular cyclization to furnish 5-(4-OMeC6H5)-4H-1,2,4-triazol-3-thiol (IV). Ultimately, IV was aralkylated at thiol position with aralkyl halides V(a-l) in polar aprotic solvent and catalytic amounts of LiH to provide S-aralkylated 5-(4-OMeC6H5)-4-phenyl-4H-1,2,4-triazol-3-thiols VI(a-l). Modern spectral analysis data explicitly established all the substitutions on nucleophilic S-atom of parent 1,2,4-triazol-3-thiol ring. Effective anti-cholinesterase potential depicted in 3-(phenylpropylthio)-5-(4-OMeC6H5)-4-phenyl-4H-1,2,4-triazole; VIc (IC50; 3.26±0.35 µM) against acetyl cholinesterase; AChE and 3-(phenethylthio)-5-(4-OMeC6H5)-4-phenyl-4H-1,2,4-triazole; VIb (IC50; 8.52±0.54 µM) against butyrylcholinesterase; BChE enzyme as compared to standard Eserine for both enzymes (IC50; 0.04±0.01 µM). Molecular modelling analyses had been conducted to recognize the interconnection of these compounds with enzymes that suggested key interactions (Docking is made to untie the active binding sites). Anti-proliferative activity results showed VIg and VIj with-Cl groups on benzylic ring as promising candidates with HCT-116 cell viability of 14.83% and 3.09% respectively.

ALZHEIMER'S disease; APROTIC solvents; BENZYLIC group; POLAR solvents; PSEUDOPOTENTIAL method; ACETYLCHOLINESTERASE

Journal of the Chemical Society of Pakistan, 2021, Vol 43, Issue 6, p694

0253-5106

Academic Journal

10.52568/000974/jcsp/43.06.2021