Synthesis, Spectral Evaluation and in Silico Studies of S-Aralkylated 5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols: As suitable Alzheimerand#39;s disease drug candidates

• Published in: Journal of the Chemical Society of Pakistan 2021, Vol.43 (6), p.694-694
• Main Authors: Muhammad Arfan, Muhammad Arfan, Sabahat Zahra Siddiqui, Sabahat Zahra Siddiqui, Muhammad Athar Abbasi, Muhammad Athar Abbasi, Aziz ur Rehman, Aziz ur Rehman, Syed Adnan Ali Shah, Syed Adnan Ali Shah, Muhammad Ashraf, Muhammad Ashraf, Khalid Mohammed Khan, Khalid Mohammed Khan, Rahman Shah Zaib Saleem and Amna Shah Zaib, Rahman Shah Zaib Saleem and Amna Shah Zaib
• Format: Article
• Language: English
• ISSN: 0253-5106
• DOI: 10.52568/000974/JCSP/43.06.2021

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; Alzheimerand#39;s disease. A synthetic strategy was instigated by esterifying 4-methoxybenzoic acid through Fisher esterificationand#39;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; 3.26and#177;0.35 μM) against acetyl cholinesterase; AChE and 3-(phenethylthio)-5-(4-OMeC6H5)-4-phenyl-4H-1,2,4-triazole; VIb (IC50; 8.52and#177;0.54 μM) against butyrylcholinesterase; BChE enzyme as compared to standard Eserine for both enzymes (IC50; 0.04and#177;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.