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Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation
Univ Sindh, Dr MA Kazi Inst Chem, Jamshoro 76080, Pakistan.
Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.ORCID iD: 0000-0002-7112-9296
Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.ORCID iD: 0000-0002-8491-5229
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2019 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 5, article id 860Article in journal (Refereed) Published
Abstract [en]

A small library of new drug-1,3,4-thiazidazole hybrid compounds (3a-3i) 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 mu M) indicates that it can be very effective, even at low concentrations. Compounds 3a-3i 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 pi-pi interactions with key amino acid residues related to Tyr124, Trp286, and Tyr341.

Place, publisher, year, edition, pages
MDPI, 2019. Vol. 24, no 5, article id 860
Keywords [en]
mixed-type AChE inhibitors, ADMET parameters, pharmacokinetics, drug-likeness, synthesis, antioxidant activity, molecular docking, 1, 3, 4-thiadiazole-drug
National Category
Pharmacology and Toxicology Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-382471DOI: 10.3390/molecules24050860ISI: 000462662900036PubMedID: 30823444OAI: oai:DiVA.org:uu-382471DiVA, id: diva2:1313202
Available from: 2019-05-02 Created: 2019-05-02 Last updated: 2019-05-02Bibliographically approved

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