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Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation.
Molecules. 2019 Feb 28; 24(5)M

Abstract

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 µM) 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 π⁻π interactions with key amino acid residues related to Tyr124, Trp286, and Tyr341.

Authors+Show Affiliations

Dr. M.A. Kazi Institute of Chemistry, University of Sindh, Jamshoro 76080, Pakistan. rabailrabailnoor@gmail.com.Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan. aamersaeed@yahoo.com.Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan. mrpervaiz@gmail.com.Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan. fayazali@chem.qau.edu.pk.Department of Physiology, University of Sindh, Jamshoro 76080, Pakistan. qamar.abbas.qau@gmail.com.Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. malajmii@ksu.edu.sa.Pharmacognosy Group, Department of Medicinal Chemistry, Biomedical Center (BMC), Uppsala University, SE-751 23 Uppsala, Sweden. Hesham.El-Seedi@fkog.uu.se.Dr. M.A. Kazi Institute of Chemistry, University of Sindh, Jamshoro 76080, Pakistan. mahboobalirind@gmail.com.Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 314-701, Korea. mubashirhassan_gcul@yahoo.com.Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 314-701, Korea. hussain_solangi@yahoo.com.Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 314-701, Korea. dnalove@kongju.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30823444

Citation

Ujan, Rabail, et al. "Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation." Molecules (Basel, Switzerland), vol. 24, no. 5, 2019.
Ujan R, Saeed A, Channar PA, et al. Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation. Molecules. 2019;24(5).
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. (2019). Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation. Molecules (Basel, Switzerland), 24(5). https://doi.org/10.3390/molecules24050860
Ujan R, et al. Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation. Molecules. 2019 Feb 28;24(5) PubMed PMID: 30823444.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation. AU - Ujan,Rabail, AU - Saeed,Aamer, AU - Channar,Pervaiz Ali, AU - Larik,Fayaz Ali, AU - Abbas,Qamar, AU - Alajmi,Mohamed F, AU - El-Seedi,Hesham R, AU - Rind,Mahboob Ali, AU - Hassan,Mubashir, AU - Raza,Hussain, AU - Seo,Sung-Yum, Y1 - 2019/02/28/ PY - 2019/01/01/received PY - 2019/02/15/revised PY - 2019/02/18/accepted PY - 2019/3/3/entrez PY - 2019/3/3/pubmed PY - 2019/6/20/medline KW - 1,3,4-thiadiazole-drug KW - ADMET parameters KW - antioxidant activity KW - drug-likeness KW - mixed-type AChE inhibitors KW - molecular docking KW - pharmacokinetics KW - synthesis JF - Molecules (Basel, Switzerland) JO - Molecules VL - 24 IS - 5 N2 - 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 µM) 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 π⁻π interactions with key amino acid residues related to Tyr124, Trp286, and Tyr341. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/30823444/Drug_134_Thiadiazole_Conjugates_as_Novel_Mixed_Type_Inhibitors_of_Acetylcholinesterase:_Synthesis_Molecular_Docking_Pharmacokinetics_and_ADMET_Evaluation_ L2 - https://www.mdpi.com/resolver?pii=molecules24050860 DB - PRIME DP - Unbound Medicine ER -