Synthesis of New Triazole-Based Thiosemicarbazone Derivatives as Anti-Alzheimer’s Disease Candidates: Evidence-Based In Vitro Study
Fazal Rahim,
Hayat Ullah,
Muhammad Taha,
Rafaqat Hussain,
Maliha Sarfraz,
Rashid Iqbal,
Naveed Iqbal,
Shoaib Khan,
Syed Adnan Ali Shah,
Marzough Aziz Albalawi,
Mahmoud A. Abdelaziz,
Fatema Suliman Alatawi,
Abdulrahman Alasmari,
Mohamed I. Sakran,
Nahla Zidan,
Ibrahim Jafri,
Khalid Mohammed Khan
Affiliations
Fazal Rahim
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan
Hayat Ullah
Department of Chemistry, University of Okara, Okara 56130, Pakistan
Muhammad Taha
Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
Rafaqat Hussain
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan
Maliha Sarfraz
Department of Zoology, Wildlife and Fisheries, Sub-Campus Toba Tek Singh, University of Agriculture Faisalabad, Punjab 36050, Pakistan
Rashid Iqbal
Department of Agronomy, Faculty of Agriculture and Environment, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan
Naveed Iqbal
Department of Chemistry, University of Poonch, Rawalakot 12350, Pakistan
Shoaib Khan
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan
Syed Adnan Ali Shah
Faculty of Pharmacy, Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, Bandar Puncak Alam 42300, Selangor, Malaysia
Marzough Aziz Albalawi
Department of Chemistry, Alwajh College, University of Tabuk, Tabuk 47512, Saudi Arabia
Mahmoud A. Abdelaziz
Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia
Fatema Suliman Alatawi
Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia
Abdulrahman Alasmari
Department of Biology, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia
Mohamed I. Sakran
Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia
Nahla Zidan
Department of Nutrition and Food Science, Faculty of Home Economics, University of Tabuk, Tabuk 71491, Saudi Arabia
Ibrahim Jafri
Department of Biotechnology, Faculty of Sciences, Taif University, Taif 21944, Saudi Arabia
Khalid Mohammed Khan
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
Triazole-based thiosemicarbazone derivatives (6a–u) were synthesized then characterized by spectroscopic techniques, such as 1HNMR and 13CNMR and HRMS (ESI). Newly synthesized derivatives were screened in vitro for inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives (except 6c and 6d, which were found to be completely inactive) demonstrated moderate to good inhibitory effects ranging from 0.10 ± 0.050 to 12.20 ± 0.30 µM (for AChE) and 0.20 ± 0.10 to 14.10 ± 0.40 µM (for BuChE). The analogue 6i (IC50 = 0.10 ± 0.050 for AChE and IC50 = 0.20 ± 0.050 µM for BuChE), which had di-substitutions (2-nitro, 3-hydroxy groups) at ring B and tri-substitutions (2-nitro, 4,5-dichloro groups) at ring C, and analogue 6b (IC50 = 0.20 ± 0.10 µM for AChE and IC50 = 0.30 ± 0.10 µM for BuChE), which had di-Cl at 4,5, -NO2 groups at 2-position of phenyl ring B and hydroxy group at ortho-position of phenyl ring C, emerged as the most potent inhibitors of both targeted enzymes (AChE and BuChE) among the current series. A structure-activity relationship (SAR) was developed based on nature, position, number, electron donating/withdrawing effects of substitution/s on phenyl rings. Molecular docking studies were used to describe binding interactions of the most active inhibitors with active sites of AChE and BuChE.