Maryam Maqbool, Mehwish Solangi, Khalid M. Khan, Musa Özil, Nimet Baltaş, Uzma Salar, Syeda S. Tariq, Zaheer Ul Haq, Muhammad Taha
{"title":"Imidazole-thiadiazole hybrids: A multitarget de novo drug design approach, in vitro evaluation, ADME/T, and in silico studies","authors":"Maryam Maqbool, Mehwish Solangi, Khalid M. Khan, Musa Özil, Nimet Baltaş, Uzma Salar, Syeda S. Tariq, Zaheer Ul Haq, Muhammad Taha","doi":"10.1002/ardp.202400325","DOIUrl":null,"url":null,"abstract":"<p>A library of imidazole-thiadiazole compounds (<b>1–24</b>) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against <i>α</i>-glucosidase, <i>α</i>-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Derivatives <b>5–7</b>, <b>9–11</b>, <b>18</b>, and <b>19</b> displayed potent inhibitory activities with IC<sub>50</sub> values of 1.4 ± 0.01 to 13.6 ± 0.01 and 0.9 ± 0.01 to 12.8 ± 0.02 µM against <i>α</i>-glucosidase, and <i>α</i>-amylase enzymes, respectively, compared to the standard acarbose (IC<sub>50</sub> = 14.8 ± 0.01 µM). Compounds <b>11–13</b>, <b>16</b>, <b>20</b>, and <b>21</b> exhibited potent activity IC<sub>50</sub> = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC<sub>50</sub> = 39.2 ± 0.05 µM). Compound <b>21</b> demonstrated comparable inhibition IC<sub>50</sub> = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC<sub>50</sub> = 44.2 ± 0.05 µM). All compounds also demonstrated excellent antioxidant activities <i>via</i> CUPRAC, FRAP, and DPPH methods. Complementing the experimental studies, extensive kinetics, ADME/T, and molecular docking analysis were also conducted to unravel the pharmacokinetics and safety profiles of the designed compounds. These studies supported the experimental findings and facilitated the prioritization of hit candidates for subsequent stages of drug development.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archiv der Pharmazie","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ardp.202400325","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
A library of imidazole-thiadiazole compounds (1–24) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Derivatives 5–7, 9–11, 18, and 19 displayed potent inhibitory activities with IC50 values of 1.4 ± 0.01 to 13.6 ± 0.01 and 0.9 ± 0.01 to 12.8 ± 0.02 µM against α-glucosidase, and α-amylase enzymes, respectively, compared to the standard acarbose (IC50 = 14.8 ± 0.01 µM). Compounds 11–13, 16, 20, and 21 exhibited potent activity IC50 = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC50 = 39.2 ± 0.05 µM). Compound 21 demonstrated comparable inhibition IC50 = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC50 = 44.2 ± 0.05 µM). All compounds also demonstrated excellent antioxidant activities via CUPRAC, FRAP, and DPPH methods. Complementing the experimental studies, extensive kinetics, ADME/T, and molecular docking analysis were also conducted to unravel the pharmacokinetics and safety profiles of the designed compounds. These studies supported the experimental findings and facilitated the prioritization of hit candidates for subsequent stages of drug development.
期刊介绍:
Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.