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 | [Journal of Chemical Society of Pakistan • 2021]

Author(s):

1. Muhammad Arfan: Department of Chemistry, Government College University,Lahore, Pakistan

2. Sabahat Zahra Siddiqui: Department of Chemistry, Government College University,Lahore,Pakistan

3. Muhammad Athar Abbasi: Department of Chemistry, Government College University,Lahore,Pakistan

4. Aziz-ur-Rehman: Department of Chemistry, Government College University, Lahore, Pakistan.

5. Syed Adnan Ali Shah: Faculty of Pharmacy & cAtta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Level 9, FF3, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia

6. Muhammad Ashraf: Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan

7. Khalid Mohammed Khan: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan

8. Rahman Shah Zaib Saleem: Department of Chemistry & Chemical Engineering, SBA School of Sciences & Engineering, Lahore University of Management Sciences, Opposite Sector-U, DHA, Lahore 54792 Pakistan.

9. Amna Shah Zaib: Rashid Latif Medical College, 35-KM, Ferozepur Road, Lahore, Pakistan

Abstract:

Summary: Our efforts lay emphasis on synthesis of S-aralkylated 5-(4-OMeC6H5)-4-phenyl-4H1,2,4-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-1,2,4triazol-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)-4phenyl-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)-4phenyl-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.

Page(s): 694-705

DOI: DOI not available

Published: Journal: Journal of Chemical Society of Pakistan, Volume: 43, Issue: 6, Year: 2021

Keywords:

spectral analysis , 4Triazole , Cholinesterase abstinence , Aralkyl halide

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