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Open AccessArticle

Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation

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Dr. M.A. Kazi Institute of Chemistry, University of Sindh, Jamshoro 76080, Pakistan
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Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
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Department of Physiology, University of Sindh, Jamshoro 76080, Pakistan
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Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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Pharmacognosy Group, Department of Medicinal Chemistry, Biomedical Center (BMC), Uppsala University, SE-751 23 Uppsala, Sweden
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Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 314-701, Korea
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Author to whom correspondence should be addressed.
Molecules 2019, 24(5), 860; https://doi.org/10.3390/molecules24050860
Received: 1 January 2019 / Revised: 15 February 2019 / Accepted: 18 February 2019 / Published: 28 February 2019
A small library of new drug-1,3,4-thiazidazole hybrid compounds (3a3i) was synthesized, characterized, and assessed for their acetyl cholinesterase enzyme (AChE) inhibitory and free radical scavenging activities. The newly synthesized derivatives showed promising activities against AChE, especially compound 3b (IC50 18.1 ± 0.9 nM), which was the most promising molecule in the series, and was substantially more active than the reference drug (neostigmine methyl sulfate; IC50 2186.5 ± 98.0 nM). Kinetic studies were performed to elucidate the mode of inhibition of the enzyme, and the compounds showed mixed-type mechanisms for inhibiting AChE. The Ki of 3b (0.0031 µM) indicates that it can be very effective, even at low concentrations. Compounds 3a3i all complied with Lipinski’s Rule of Five, and showed high drug-likeness scores. The pharmacokinetic parameters revealed notable lead-like properties with insignificant liver and skin-penetrating effects. The structure–activity relationship (SAR) analysis indicated π–π interactions with key amino acid residues related to Tyr124, Trp286, and Tyr341. View Full-Text
Keywords: mixed-type AChE inhibitors; ADMET parameters; pharmacokinetics; drug-likeness; synthesis; antioxidant activity; molecular docking; 1,3,4-thiadiazole-drug mixed-type AChE inhibitors; ADMET parameters; pharmacokinetics; drug-likeness; synthesis; antioxidant activity; molecular docking; 1,3,4-thiadiazole-drug
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Ujan, R.; Saeed, A.; Channar, P.A.; Larik, F.A.; Abbas, Q.; Alajmi, M.F.; El-Seedi, H.R.; Rind, M.A.; Hassan, M.; Raza, H.; Seo, S.-Y. Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation. Molecules 2019, 24, 860.

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