Multipotent Cholinesterase Inhibitors for the Treatment of Alzheimer’s Disease: Synthesis, Biological Analysis and Molecular Docking Study of Benzimidazole-Based Thiazole Derivatives
Rafaqat Hussain,
Hayat Ullah,
Fazal Rahim,
Maliha Sarfraz,
Muhammad Taha,
Rashid Iqbal,
Wajid Rehman,
Shoaib Khan,
Syed Adnan Ali Shah,
Sajjad Hyder,
Majid Alhomrani,
Abdulhakeem S. Alamri,
Osama Abdulaziz,
Mahmoud A. Abdelaziz
Affiliations
Rafaqat Hussain
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan
Hayat Ullah
Department of Chemistry, University of Okara, Okara 56300, Pakistan
Fazal Rahim
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan
Maliha Sarfraz
Department of Zoology, Wildlife and Fisheries, University of Agriculture Faisalabad, Sub-Campus Toba Tek Singh, Punjab 36050, Pakistan
Muhammad Taha
Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
Rashid Iqbal
Department of Agronomy, Faculty of Agriculture and Environment, The Islamia University of Bahawalpur Pakistan, Bahawalpur 63100, Pakistan
Wajid Rehman
Department of Chemistry, Hazara University, Mansehra 21120, 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
Sajjad Hyder
Department of Botany, Government College Women University, Sialkot 51310, Pakistan
Majid Alhomrani
Department of Clinical Laboratories Sciences, The Faculty of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
Abdulhakeem S. Alamri
Department of Clinical Laboratories Sciences, The Faculty of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
Osama Abdulaziz
Department of Clinical Laboratories Sciences, The Faculty of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
Mahmoud A. Abdelaziz
Department of Chemistry, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
Twenty-four analogues of benzimidazole-based thiazoles (1–24) were synthesized and assessed for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory potential. All analogues were found to exhibit good inhibitory potential against cholinesterase enzymes, having IC50 values in the ranges of 0.10 ± 0.05 to 11.10 ± 0.30 µM (for AChE) and 0.20 ± 0.050 µM to 14.20 ± 0.10 µM (for BuChE) as compared to the standard drug Donepezil (IC50 = 2.16 ± 0.12 and 4.5 ± 0.11 µM, respectively). Among the series, analogues 16 and 21 were found to be the most potent inhibitors of AChE and BuChE enzymes. The number (s), types, electron-donating or -withdrawing effects and position of the substituent(s) on the both phenyl rings B & C were the primary determinants of the structure-activity relationship (SAR). In order to understand how the most active derivatives interact with the amino acids in the active site of the enzyme, molecular docking studies were conducted. The results obtained supported the experimental data. Additionally, the structures of all newly synthesized compounds were elucidated by using several spectroscopic methods like 13C-NMR, 1H-NMR and HR EIMS.
