作为抗菌剂的一些偶氮唑衍生物的设计、硅学研究和合成

IF 0.3 Q4 CHEMISTRY, MULTIDISCIPLINARY Oriental Journal Of Chemistry Pub Date : 2023-12-27 DOI:10.13005/ojc/390618
Syeda Huma H. Zaidi, Abida Ash Mohd, Mohd Imran, Menwah Khalifah Alshammari, Khattab Fahed Alfrah
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引用次数: 0

摘要

这项研究旨在发现更安全、更有效的三唑哒嗪酮杂化(TP)化合物,作为甾醇 14α- 去甲基化酶(SDM)的抑制剂。研究人员设计了 33 种 TP(TP1 至 TP33)的化学结构。利用三种不同的 SDM 蛋白(PDB IDs:3LD6、5FSA 和 5TZ1),通过分子对接软件确定了 TPs 的对接分数(DS)。ProTox II 网络服务器预测了 TPs 的口服半数致死剂量(LD50)和毒性等级(TC),而 Swiss-ADME 数据库则预测了它们的药代动力学参数。根据硅学研究数据,合成了四种 TPs(TP18、TP22、TP27 和 TP33),并评估了它们对七种真菌的体外抗真菌活性。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)和 TP33(3LD6 = -8.19;5FSA = -8.98;5TZ1 = -9.94)优于氟康唑(3LD6 = -8.18;5FSA = -8.79;5TZ1 = -9.18)和酮康唑(3LD6 = -8.16;5FSA = -8.86;5TZ1 = -9.06)的 DS,这意味着 TP18、TP22、TP27 和 TP33 比氟康唑和酮康唑对 SDM 具有更高的效力。TP18(500 毫克/千克;TC 4)、TP22(500 毫克/千克;TC 4)、TP27(1000 毫克/千克;TC 4)和 TP33(1000 毫克/千克;TC 4)的预期半数致死剂量和毒性等级(TC)均优于酮康唑(166 毫克/千克;TC 3)。瑞士-ADME 数据库的结果表明,TP18、TP22、TP27 和 TP33 通过了 Lipinski 的药物亲和性规则,其口服吸收率和生物利用度与酮康唑和氟康唑相当。合成化合物的光谱数据(傅立叶变换红外光谱、1H-核磁共振、13C-核磁共振和质谱)与其设计的化学结构相符。抗真菌活性数据表明,TP18、TP22、TP27 和 TP33 是比氟康唑和酮康唑更好的抗真菌剂。这些发现与 TP18、TP22、TP27 和 TP33 的 DS 相吻合。总之,TP18、TP22、TP27 和 TP33 代表了一种新的化学模板,可用于开发更安全、更好的 SDM 抑制剂作为抗真菌剂。
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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.
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来源期刊
Oriental Journal Of Chemistry
Oriental Journal Of Chemistry CHEMISTRY, MULTIDISCIPLINARY-
自引率
20.00%
发文量
172
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.
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