Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation
A small library of new drug-1,3,4-thiazidazole hybrid compounds (<b>3a</b>⁻<b>3i</b>) was synthesized, characterized, and assessed for their acetyl cholinesterase enzyme (AChE) inhibitory and free radical scavenging activities. The newly synthesized derivatives show...
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MDPI AG
2019-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/5/860 |
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doaj-08241e4e835f403db7fb633113bd44972020-11-25T02:11:08ZengMDPI AGMolecules1420-30492019-02-0124586010.3390/molecules24050860molecules24050860Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET EvaluationRabail Ujan0Aamer Saeed1Pervaiz Ali Channar2Fayaz Ali Larik3Qamar Abbas4Mohamed F. Alajmi5Hesham R. El-Seedi6Mahboob Ali Rind7Mubashir Hassan8Hussain Raza9Sung-Yum Seo10Dr. M.A. Kazi Institute of Chemistry, University of Sindh, Jamshoro 76080, PakistanDepartment of Chemistry, Quaid-I-Azam University, Islamabad 45320, PakistanDepartment of Chemistry, Quaid-I-Azam University, Islamabad 45320, PakistanDepartment of Chemistry, Quaid-I-Azam University, Islamabad 45320, PakistanDepartment of Physiology, University of Sindh, Jamshoro 76080, PakistanDepartment of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaPharmacognosy Group, Department of Medicinal Chemistry, Biomedical Center (BMC), Uppsala University, SE-751 23 Uppsala, SwedenDr. M.A. Kazi Institute of Chemistry, University of Sindh, Jamshoro 76080, PakistanDepartment of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 314-701, KoreaDepartment of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 314-701, KoreaDepartment of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 314-701, KoreaA small library of new drug-1,3,4-thiazidazole hybrid compounds (<b>3a</b>⁻<b>3i</b>) 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 <b>3b</b> (IC<sub>50</sub> 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; IC<sub>50</sub> 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 <i>K</i>i of <b>3b</b> (0.0031 µM) indicates that it can be very effective, even at low concentrations. Compounds <b>3a</b>⁻<b>3i</b> 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.https://www.mdpi.com/1420-3049/24/5/860mixed-type AChE inhibitorsADMET parameterspharmacokineticsdrug-likenesssynthesisantioxidant activitymolecular docking1,3,4-thiadiazole-drug |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Rabail Ujan Aamer Saeed Pervaiz Ali Channar Fayaz Ali Larik Qamar Abbas Mohamed F. Alajmi Hesham R. El-Seedi Mahboob Ali Rind Mubashir Hassan Hussain Raza Sung-Yum Seo |
| spellingShingle |
Rabail Ujan Aamer Saeed Pervaiz Ali Channar Fayaz Ali Larik Qamar Abbas Mohamed F. Alajmi Hesham R. El-Seedi Mahboob Ali Rind Mubashir Hassan Hussain Raza Sung-Yum Seo Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation Molecules mixed-type AChE inhibitors ADMET parameters pharmacokinetics drug-likeness synthesis antioxidant activity molecular docking 1,3,4-thiadiazole-drug |
| author_facet |
Rabail Ujan Aamer Saeed Pervaiz Ali Channar Fayaz Ali Larik Qamar Abbas Mohamed F. Alajmi Hesham R. El-Seedi Mahboob Ali Rind Mubashir Hassan Hussain Raza Sung-Yum Seo |
| author_sort |
Rabail Ujan |
| title |
Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation |
| title_short |
Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation |
| title_full |
Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation |
| title_fullStr |
Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation |
| title_full_unstemmed |
Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation |
| title_sort |
drug-1,3,4-thiadiazole conjugates as novel mixed-type inhibitors of acetylcholinesterase: synthesis, molecular docking, pharmacokinetics, and admet evaluation |
| publisher |
MDPI AG |
| series |
Molecules |
| issn |
1420-3049 |
| publishDate |
2019-02-01 |
| description |
A small library of new drug-1,3,4-thiazidazole hybrid compounds (<b>3a</b>⁻<b>3i</b>) 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 <b>3b</b> (IC<sub>50</sub> 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; IC<sub>50</sub> 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 <i>K</i>i of <b>3b</b> (0.0031 µM) indicates that it can be very effective, even at low concentrations. Compounds <b>3a</b>⁻<b>3i</b> 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. |
| topic |
mixed-type AChE inhibitors ADMET parameters pharmacokinetics drug-likeness synthesis antioxidant activity molecular docking 1,3,4-thiadiazole-drug |
| url |
https://www.mdpi.com/1420-3049/24/5/860 |
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