Synthesis, highly potent α-glucosidase inhibition, antioxidant and molecular docking of various novel dihydropyrimidine derivatives to treat diabetes mellitus
{"title":"Synthesis, highly potent α-glucosidase inhibition, antioxidant and molecular docking of various novel dihydropyrimidine derivatives to treat diabetes mellitus","authors":"Masooma Abbas, Nuzhat Arshad","doi":"10.1016/j.bmcl.2024.130016","DOIUrl":null,"url":null,"abstract":"<div><div>1,4-dihydropyrimidine-2-thiones were synthesized in five series that include 5-carboxylic acid derivatives of dihydropyrimidine (series A, <strong>6</strong>–<strong>8</strong>), novel 5-carboxamide derivatives of dihydropyrimidine (series B, <strong>9</strong>–<strong>14</strong>), N,S<strong>-</strong>dimethyl<strong>-</strong>dihydropyrimidine (series C, <strong>15</strong>–<strong>20)</strong>, <em>N</em>-hydrazinyl derivatives of dihydropyrimidine (series D, <strong>21</strong>–<strong>24)</strong> and tetrazolo dihydropyrimidine derivatives (series E, <strong>25</strong>–<strong>28</strong>), and evaluated for anti-diabetic capability. The prepared novel compounds were structurally established by FTIR, <sup>1</sup>HNMR, <sup>13</sup>CNMR, ESI and HRMS. All of these compounds from series A—E were first time examined for α-glucosidase inhibition as to evaluate their anti-diabetic potential. Most of the compounds for example <strong>8, 11</strong>–<strong>14, 15, 17</strong>–<strong>21, 25 and 28</strong> demonstrated greater α-glucosidase inhibitory effects (IC<sub>50</sub> = 12.5 ± 0.21 to 47.3 ± 0.23 μM) when compared to deoxynojirimycin as standard (IC<sub>50</sub> = 52.02 ± 0.36 μM). Compounds from series B and C found to be highly active however, the compounds from series D found generally less active. The structure–activity relationships demonstrated the importance of C-5 carboxamides, C-5 ethyl ester functionality, and the presence of N,S-dimethyl groups at pyrimidine ring for α-glucosidase inhibition. The docking studies demonstrated that all the active compounds have <em>van der Waals</em> and alkyl bonds interactions with the targeted site of the human lysosomal acid α-glucosidase. All these compounds were also tested for antioxidant potential by DPPH radical scavenging protocol that exhibited significant antioxidant effects (IC<sub>50</sub> = 21.4 <span><math><mo>±</mo></math></span> 0.45 to 92.1 <span><math><mo>±</mo></math></span> 0.38 μM) as compared to the standard butylated hydroxyanisol (IC<sub>50</sub> = 44.2 <span><math><mo>±</mo></math></span> 0.36 μM). Among all, compound <strong>13, 14 and 19</strong> with potent α-glucosidase inhibition (IC<sub>50</sub> = 18.9 ± 0.72, 23.3 ± 0.45 and 21.5 ± 0.16 µM, respectively) along with excellent antioxidant potential in the range of (IC<sub>50</sub> = 21.4 <span><math><mo>±</mo></math></span> 0.45 to 31.2 ± 0.23 μM) indicated their ability to use as valuable leads for the development of anti-diabetic drugs with the combined effects of antioxidants.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130016"},"PeriodicalIF":2.5000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X24004189","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
1,4-dihydropyrimidine-2-thiones were synthesized in five series that include 5-carboxylic acid derivatives of dihydropyrimidine (series A, 6–8), novel 5-carboxamide derivatives of dihydropyrimidine (series B, 9–14), N,S-dimethyl-dihydropyrimidine (series C, 15–20), N-hydrazinyl derivatives of dihydropyrimidine (series D, 21–24) and tetrazolo dihydropyrimidine derivatives (series E, 25–28), and evaluated for anti-diabetic capability. The prepared novel compounds were structurally established by FTIR, 1HNMR, 13CNMR, ESI and HRMS. All of these compounds from series A—E were first time examined for α-glucosidase inhibition as to evaluate their anti-diabetic potential. Most of the compounds for example 8, 11–14, 15, 17–21, 25 and 28 demonstrated greater α-glucosidase inhibitory effects (IC50 = 12.5 ± 0.21 to 47.3 ± 0.23 μM) when compared to deoxynojirimycin as standard (IC50 = 52.02 ± 0.36 μM). Compounds from series B and C found to be highly active however, the compounds from series D found generally less active. The structure–activity relationships demonstrated the importance of C-5 carboxamides, C-5 ethyl ester functionality, and the presence of N,S-dimethyl groups at pyrimidine ring for α-glucosidase inhibition. The docking studies demonstrated that all the active compounds have van der Waals and alkyl bonds interactions with the targeted site of the human lysosomal acid α-glucosidase. All these compounds were also tested for antioxidant potential by DPPH radical scavenging protocol that exhibited significant antioxidant effects (IC50 = 21.4 0.45 to 92.1 0.38 μM) as compared to the standard butylated hydroxyanisol (IC50 = 44.2 0.36 μM). Among all, compound 13, 14 and 19 with potent α-glucosidase inhibition (IC50 = 18.9 ± 0.72, 23.3 ± 0.45 and 21.5 ± 0.16 µM, respectively) along with excellent antioxidant potential in the range of (IC50 = 21.4 0.45 to 31.2 ± 0.23 μM) indicated their ability to use as valuable leads for the development of anti-diabetic drugs with the combined effects of antioxidants.
期刊介绍:
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.