Afshan Gul, Syed Muhammad Saad, Humaira Zafar, Atia-Tul-Wahab, Khalid Mohammed Khan, M Iqbal Choudhary
{"title":"3-芳基-2-硫氧基-2,3-二氢喹唑啉-4(1H)- 1衍生物的体外和体内黄嘌呤氧化酶抑制活性。","authors":"Afshan Gul, Syed Muhammad Saad, Humaira Zafar, Atia-Tul-Wahab, Khalid Mohammed Khan, M Iqbal Choudhary","doi":"10.2174/1573406418666220620124034","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Hyperuricemia is associated with several disease conditions, such as atherosclerosis, arthritis, kidney stones, and many others. Xanthine oxidase (XO) is an enzyme that catalyzes the conversion of xanthine to uric acid. Hence, XO is a major therapeutic drug target in the treatment of hyperuricemia and associated disorders.</p><p><strong>Objectives: </strong>The current study aimed to identify XO inhibitors based on quinazoline derivatives, with the potential to be used against gout and other hyperuricemia-associated diseases.</p><p><strong>Methods: </strong>In the current study, eighteen quinazoline derivatives 2-19 were synthesized and assessed for their in vitro xanthine Oxidase (XO) inhibitory activity. Furthermore, the most active compounds, 5 and 17, were subjected to kinetics studies, followed by computational docking. Human BJ fibroblast cells were used to measure the cytotoxicity of active compounds.</p><p><strong>Results: </strong>Compounds 4-6, 8, 10, 13, 15-17, and 19 were found active against XO, with an IC<sub>50</sub> values between 33.688 to 362.173μM. The obtained results showed that compounds 5 and 17 possess a significant xanthine oxidase inhibitory activity. The kinetics and molecular docking studies suggested that compounds 5 (IC<sub>50</sub> = 39.904 ± 0.21 μM) and 17 (IC<sub>50</sub> = 33.688 ± 0.30 μM) bind in the allosteric site of XO and exhibit a non-competitive type of inhibition. The molecular docking studies also predicted that the NH group of the pyrimidine ring binds with Ser344 residues of XO. Furthermore, all active compounds were non-cytotoxic on the human BJ fibroblasts cell line.</p><p><strong>Conclusion: </strong>This study identifies a series of quinazoline compounds as xanthine oxidase inhibitors, with the potential to be further investigated.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"<i>In vitro</i> and <i>In silico</i> Xanthine Oxidase Inhibitory Activities of 3-Aryl-2- thioxo-2,3-dihydroquinazolin-4(1H)-one Derivatives.\",\"authors\":\"Afshan Gul, Syed Muhammad Saad, Humaira Zafar, Atia-Tul-Wahab, Khalid Mohammed Khan, M Iqbal Choudhary\",\"doi\":\"10.2174/1573406418666220620124034\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Hyperuricemia is associated with several disease conditions, such as atherosclerosis, arthritis, kidney stones, and many others. Xanthine oxidase (XO) is an enzyme that catalyzes the conversion of xanthine to uric acid. Hence, XO is a major therapeutic drug target in the treatment of hyperuricemia and associated disorders.</p><p><strong>Objectives: </strong>The current study aimed to identify XO inhibitors based on quinazoline derivatives, with the potential to be used against gout and other hyperuricemia-associated diseases.</p><p><strong>Methods: </strong>In the current study, eighteen quinazoline derivatives 2-19 were synthesized and assessed for their in vitro xanthine Oxidase (XO) inhibitory activity. Furthermore, the most active compounds, 5 and 17, were subjected to kinetics studies, followed by computational docking. Human BJ fibroblast cells were used to measure the cytotoxicity of active compounds.</p><p><strong>Results: </strong>Compounds 4-6, 8, 10, 13, 15-17, and 19 were found active against XO, with an IC<sub>50</sub> values between 33.688 to 362.173μM. The obtained results showed that compounds 5 and 17 possess a significant xanthine oxidase inhibitory activity. The kinetics and molecular docking studies suggested that compounds 5 (IC<sub>50</sub> = 39.904 ± 0.21 μM) and 17 (IC<sub>50</sub> = 33.688 ± 0.30 μM) bind in the allosteric site of XO and exhibit a non-competitive type of inhibition. The molecular docking studies also predicted that the NH group of the pyrimidine ring binds with Ser344 residues of XO. Furthermore, all active compounds were non-cytotoxic on the human BJ fibroblasts cell line.</p><p><strong>Conclusion: </strong>This study identifies a series of quinazoline compounds as xanthine oxidase inhibitors, with the potential to be further investigated.</p>\",\"PeriodicalId\":18382,\"journal\":{\"name\":\"Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/1573406418666220620124034\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/1573406418666220620124034","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
In vitro and In silico Xanthine Oxidase Inhibitory Activities of 3-Aryl-2- thioxo-2,3-dihydroquinazolin-4(1H)-one Derivatives.
Background: Hyperuricemia is associated with several disease conditions, such as atherosclerosis, arthritis, kidney stones, and many others. Xanthine oxidase (XO) is an enzyme that catalyzes the conversion of xanthine to uric acid. Hence, XO is a major therapeutic drug target in the treatment of hyperuricemia and associated disorders.
Objectives: The current study aimed to identify XO inhibitors based on quinazoline derivatives, with the potential to be used against gout and other hyperuricemia-associated diseases.
Methods: In the current study, eighteen quinazoline derivatives 2-19 were synthesized and assessed for their in vitro xanthine Oxidase (XO) inhibitory activity. Furthermore, the most active compounds, 5 and 17, were subjected to kinetics studies, followed by computational docking. Human BJ fibroblast cells were used to measure the cytotoxicity of active compounds.
Results: Compounds 4-6, 8, 10, 13, 15-17, and 19 were found active against XO, with an IC50 values between 33.688 to 362.173μM. The obtained results showed that compounds 5 and 17 possess a significant xanthine oxidase inhibitory activity. The kinetics and molecular docking studies suggested that compounds 5 (IC50 = 39.904 ± 0.21 μM) and 17 (IC50 = 33.688 ± 0.30 μM) bind in the allosteric site of XO and exhibit a non-competitive type of inhibition. The molecular docking studies also predicted that the NH group of the pyrimidine ring binds with Ser344 residues of XO. Furthermore, all active compounds were non-cytotoxic on the human BJ fibroblasts cell line.
Conclusion: This study identifies a series of quinazoline compounds as xanthine oxidase inhibitors, with the potential to be further investigated.
期刊介绍:
Aims & Scope
Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.