Syeda Huma H. Zaidi, Abida Ash Mohd, Mohd Imran, Menwah Khalifah Alshammari, Khattab Fahed Alfrah
{"title":"作为抗菌剂的一些偶氮唑衍生物的设计、硅学研究和合成","authors":"Syeda Huma H. Zaidi, Abida Ash Mohd, Mohd Imran, Menwah Khalifah Alshammari, Khattab Fahed Alfrah","doi":"10.13005/ojc/390618","DOIUrl":null,"url":null,"abstract":"This work relates to the discovery of safer and more potent triazole-pyridazinone hybrid (TP) compounds as an inhibitor of sterol 14α-demethylase (SDM). The chemical structures of thirty-three TPs (TP1 to TP33) were designed. The docking scores (DS) of TPs were determined by molecular docking software utilizing three different proteins of SDM (PDB IDs: 3LD6, 5FSA, and 5TZ1). The ProTox II web server predicted TPs' oral LD50 and toxicity class (TC), whereas the Swiss-ADME database anticipated their pharmacokinetic parameters. Based on the in silico study data, four TPs (TP18, TP22, TP27, and TP33) were synthesized and evaluated for their in vitro antifungal activity against seven fungi. The DS (kcal/mol) of TP18 (3LD6 = -8.27; 5FSA = -9.07; 5TZ1 = -9.42), TP22 (3LD6 = -8.23; 5FSA = -8.93; 5TZ1 = -9.57), TP27 (3LD6 = -8.31; 5FSA = -9.12; 5TZ1 = -9.38), and TP33 (3LD6 = -8.19; 5FSA = -8.98; 5TZ1 = -9.94) were better than the DS of fluconazole (3LD6 = -8.18; 5FSA = -8.79; 5TZ1 = -9.18) and ketoconazole (3LD6 = -8.16; 5FSA = -8.86; 5TZ1 = -9.06) implying high potency of TP18, TP22, TP27 and TP33 than fluconazole and ketoconazole against SDM. The anticipated LD50 and toxicity class (TC) of TP18 (500 mg/kg; TC 4), TP22 (500 mg/kg; TC 4), TP27 (1000 mg/kg; TC 4), and TP33 (1000 mg/kg; TC 4) was better than ketoconazole (166 mg/kg; TC 3). The Swiss-ADME database results revealed that TP18, TP22, TP27, and TP33 passed Lipinski’s drug-likeliness rule and demonstrated high oral absorption and bioavailability comparable to ketoconazole and fluconazole. The synthesized compounds' spectral data (FTIR, 1H-NMR, 13C-NMR, and Mass) aligned to their designed chemical structure. The antifungal activity data implies that TP18, TP22, TP27, and TP33 were better antifungal agents than fluconazole and ketoconazole against tested fungi. These findings concurred with the DS of TP18, TP22, TP27, and TP33. In conclusion, TP18, TP22, TP27, and TP33 represent a new chemical template for developing safer and better SDM inhibitors as antifungal agents.","PeriodicalId":19599,"journal":{"name":"Oriental Journal Of Chemistry","volume":"126 S10","pages":""},"PeriodicalIF":0.3000,"publicationDate":"2023-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design, In Silico Studies, and Synthesis of Some Azole Derivatives as Antimicrobial Agents\",\"authors\":\"Syeda Huma H. Zaidi, Abida Ash Mohd, Mohd Imran, Menwah Khalifah Alshammari, Khattab Fahed Alfrah\",\"doi\":\"10.13005/ojc/390618\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"This work relates to the discovery of safer and more potent triazole-pyridazinone hybrid (TP) compounds as an inhibitor of sterol 14α-demethylase (SDM). The chemical structures of thirty-three TPs (TP1 to TP33) were designed. The docking scores (DS) of TPs were determined by molecular docking software utilizing three different proteins of SDM (PDB IDs: 3LD6, 5FSA, and 5TZ1). The ProTox II web server predicted TPs' oral LD50 and toxicity class (TC), whereas the Swiss-ADME database anticipated their pharmacokinetic parameters. Based on the in silico study data, four TPs (TP18, TP22, TP27, and TP33) were synthesized and evaluated for their in vitro antifungal activity against seven fungi. The DS (kcal/mol) of TP18 (3LD6 = -8.27; 5FSA = -9.07; 5TZ1 = -9.42), TP22 (3LD6 = -8.23; 5FSA = -8.93; 5TZ1 = -9.57), TP27 (3LD6 = -8.31; 5FSA = -9.12; 5TZ1 = -9.38), and TP33 (3LD6 = -8.19; 5FSA = -8.98; 5TZ1 = -9.94) were better than the DS of fluconazole (3LD6 = -8.18; 5FSA = -8.79; 5TZ1 = -9.18) and ketoconazole (3LD6 = -8.16; 5FSA = -8.86; 5TZ1 = -9.06) implying high potency of TP18, TP22, TP27 and TP33 than fluconazole and ketoconazole against SDM. The anticipated LD50 and toxicity class (TC) of TP18 (500 mg/kg; TC 4), TP22 (500 mg/kg; TC 4), TP27 (1000 mg/kg; TC 4), and TP33 (1000 mg/kg; TC 4) was better than ketoconazole (166 mg/kg; TC 3). The Swiss-ADME database results revealed that TP18, TP22, TP27, and TP33 passed Lipinski’s drug-likeliness rule and demonstrated high oral absorption and bioavailability comparable to ketoconazole and fluconazole. The synthesized compounds' spectral data (FTIR, 1H-NMR, 13C-NMR, and Mass) aligned to their designed chemical structure. The antifungal activity data implies that TP18, TP22, TP27, and TP33 were better antifungal agents than fluconazole and ketoconazole against tested fungi. These findings concurred with the DS of TP18, TP22, TP27, and TP33. In conclusion, TP18, TP22, TP27, and TP33 represent a new chemical template for developing safer and better SDM inhibitors as antifungal agents.\",\"PeriodicalId\":19599,\"journal\":{\"name\":\"Oriental Journal Of Chemistry\",\"volume\":\"126 S10\",\"pages\":\"\"},\"PeriodicalIF\":0.3000,\"publicationDate\":\"2023-12-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Oriental Journal Of Chemistry\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.13005/ojc/390618\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Oriental Journal Of Chemistry","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.13005/ojc/390618","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Design, In Silico Studies, and Synthesis of Some Azole Derivatives as Antimicrobial Agents
This work relates to the discovery of safer and more potent triazole-pyridazinone hybrid (TP) compounds as an inhibitor of sterol 14α-demethylase (SDM). The chemical structures of thirty-three TPs (TP1 to TP33) were designed. The docking scores (DS) of TPs were determined by molecular docking software utilizing three different proteins of SDM (PDB IDs: 3LD6, 5FSA, and 5TZ1). The ProTox II web server predicted TPs' oral LD50 and toxicity class (TC), whereas the Swiss-ADME database anticipated their pharmacokinetic parameters. Based on the in silico study data, four TPs (TP18, TP22, TP27, and TP33) were synthesized and evaluated for their in vitro antifungal activity against seven fungi. The DS (kcal/mol) of TP18 (3LD6 = -8.27; 5FSA = -9.07; 5TZ1 = -9.42), TP22 (3LD6 = -8.23; 5FSA = -8.93; 5TZ1 = -9.57), TP27 (3LD6 = -8.31; 5FSA = -9.12; 5TZ1 = -9.38), and TP33 (3LD6 = -8.19; 5FSA = -8.98; 5TZ1 = -9.94) were better than the DS of fluconazole (3LD6 = -8.18; 5FSA = -8.79; 5TZ1 = -9.18) and ketoconazole (3LD6 = -8.16; 5FSA = -8.86; 5TZ1 = -9.06) implying high potency of TP18, TP22, TP27 and TP33 than fluconazole and ketoconazole against SDM. The anticipated LD50 and toxicity class (TC) of TP18 (500 mg/kg; TC 4), TP22 (500 mg/kg; TC 4), TP27 (1000 mg/kg; TC 4), and TP33 (1000 mg/kg; TC 4) was better than ketoconazole (166 mg/kg; TC 3). The Swiss-ADME database results revealed that TP18, TP22, TP27, and TP33 passed Lipinski’s drug-likeliness rule and demonstrated high oral absorption and bioavailability comparable to ketoconazole and fluconazole. The synthesized compounds' spectral data (FTIR, 1H-NMR, 13C-NMR, and Mass) aligned to their designed chemical structure. The antifungal activity data implies that TP18, TP22, TP27, and TP33 were better antifungal agents than fluconazole and ketoconazole against tested fungi. These findings concurred with the DS of TP18, TP22, TP27, and TP33. In conclusion, TP18, TP22, TP27, and TP33 represent a new chemical template for developing safer and better SDM inhibitors as antifungal agents.
期刊介绍:
Oriental Journal of Chemistry was started in 1985 with the aim to promote chemistry research. The journal consists of articles which are rigorously peer-reviewed. The journal was indexed in Emerging Science citation index in 2016. The Editorial board member consists of eminent international scientist in all fields of Chemistry. Details of each member and their contact information is mentioned in website. The journal has thorough ethics policies and uses plagiarism detection software(ithenticate) to screen each submission. The journal has recently partnered with publons as a part of making our reviews more transparent. The journal has recently incorporated PlumX for article level matrix. The journal is promoting research on all social and academic platforms mentioned in PlumX guidelines. The journal uses google maps to improve on the geographical distribution of Editorial board members as well as authors.