Synthesis, DFT Studies, Molecular Docking and Biological Activity Evaluation of Thiazole-Sulfonamide Derivatives as Potent Alzheimer’s Inhibitors

Abstract

Alzheimer’s disease is a major public brain condition that has resulted in many deaths, as revealed by the World Health Organization (WHO). Conventional Alzheimer’s treatments such as chemotherapy, surgery, and radiotherapy are not very effective and are usually associated with several adverse effects. Therefore, it is necessary to find a new therapeutic approach that completely treats Alzheimer’s disease without many side effects. In this research project, we report the synthesis and biological activities of some new thiazole-bearing sulfonamide analogs (1–21) as potent anti-Alzheimer’s agents. Suitable characterization techniques were employed, and the density functional theory (DFT) computational approach, as well as in-silico molecular modeling, has been employed to assess the electronic properties and anti-Alzheimer’s potency of the analogs. All analogs exhibited a varied degree of inhibitory potential, but analog 1 was found to have excellent potency (IC50 = 0.10 ± 0.05µM for AChE) and (IC50 = 0.20 ± 0.050 µM for BuChE) as compared to the reference drug donepezil (IC50 = 2.16 ± 0.12 µM and 4.5 ± 0.11 µM). The structure-activity relationship was established, and it mainly depends upon the nature, position, number, and electron-donating/-withdrawing effects of the substituent/s on the phenyl rings.

Structure‐based design of new N‐benzyl‐piperidine derivatives as multitarget‐directed AChE/BuChE inhibitors for Alzheimer's disease

“…BuChE‐drug 1 complex was also stabilized by interactions with Tyr128 and His438 (Figure 6A). These results are corroborated by previously reported data describing the molecular recognition between donepezil ( 1 ) and BuChE 52–54 . Regarding molecular docking within BuChE, the N ‐benzyl‐piperidine fragment of all derivatives 4a−d presented an inverted orientation (Figure 6B and Supporting Information: Figure S5) when compared to the prototype donepezil ( 1 ).…”

“…These results are corroborated by previously reported data describing the molecular recognition between donepezil (1) and BuChE. [52][53][54] Regarding molecular docking within BuChE, the N-benzylpiperidine fragment of all derivatives 4a−d presented an inverted orientation (Figure 6B and Supporting Information: Figure S5) when compared to the prototype donepezil (1). As exemplified by BuChE-4a docking pose (Figure 6B), the addition of one more bond rotation in the structure of 4a−d possibly resulted in the different orientation and conformation.…”

Tailoring of novel morpholine-sulphonamide linked thiazole moieties as dual targeting DHFR/DNA gyrase inhibitors: synthesis, antimicrobial and antibiofilm activities, and DFT with molecular modelling studies

“…The thiazole nucleus is present in many FDAapproved drugs, such as penicillin, ceftazidime, cefepime, aztreonam, and sulfathiazole (as antibiotics), abafungin (as an antifungal), ritonavir (as an anti-HIV), bleomycin (a cancer medication), pramipexole (Parkinson's disease treatment), dasatinib (chronic myeloid leukaemia treatment), meloxicam (a nonsteroidal antiinflammatory medication), nizatidine (a peptic ulcer treatment), thiamine (vitamin B 1 , as an essential micronutrient), etc. [19][20][21][22][23][24] Also importantly, it has been proven in the literature that thiazole-based sulfonamides are potent bioactive small molecules endowed with distinct inhibitory activities against several target enzymes such as carbonic anhydrase (as antiglaucoma, anticancer, etc. ), 20,25,26 SMYD3 (as anticancer), 27 aldose reductase (as antidiabetic cataract), 23 and acetylcholinesterase with butyrylcholinesterase (as anti-Alzheimer's).…”

“…), 20,25,26 SMYD3 (as anticancer), 27 aldose reductase (as antidiabetic cataract), 23 and acetylcholinesterase with butyrylcholinesterase (as anti-Alzheimer's). 19 Most crucially, thiazole-based sulfonamides serve as promising antimicrobial agents with low minimum inhibitory concentrations (MICs) and superior activity as antibiofilms against multidrug-resistant organisms (MDROs). 28,29 Keeping in mind the aforementioned biochemical significance of sulfonamide and thiazole analogs, DNA gyrase and DHFR inhibitor-based hybrid derivatives of them are quite rare in the literature, to the best of our knowledge.…”

A Comprehensive Investigation into the Crystallology, Molecule, and Quantum Chemistry Properties of Two New Hydrous Long-Chain Dibasic Ammonium Salts CnH2n+8N2O6 (n = 35 and 37)

“…However, the synthesis of long-chain binary ammonium salts with 1,3-propanediamine and long-chain fatty acids as ligands has not been reported. The study of binary ammonium salt by quantum chemical calculation [ 42 , 43 , 44 , 45 ] has never been reported.…”