Saeed Sadaf, Shahzadi Irum, Zahoor Ameer Fawad, Al-Mutairi Aamal A, Kamal Shagufta, Faisal Shah, Irfan Ali, Al-Hussain Sami A, Muhammed Muhammed Tilahun, Zaki Magdi E A
Department of Chemistry, Government College University Faisalabad, Faisalabad, Pakistan.
Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.
Front Chem. 2024 Apr 5;12:1372378. doi: 10.3389/fchem.2024.1372378. eCollection 2024.
Theophylline, a nitrogen-containing heterocycle, serves as a promising focal point for medicinal researchers aiming to create derivatives with diverse pharmacological applications. In this work, we present an improved synthetic method for a range of theophylline-1,2,4-triazole-S-linked N-phenyl acetamides (4a‒g) utilizing ultrasound-assisted synthetic approach. The objective was to assess the effectiveness of synthesized theophylline-1,2,4-triazoles (4a‒g) as inhibitors of HCV serine protease and as antibacterial agents against QB-928 and AB-274. Theophylline-1,2,4-triazoles were obtained in good to excellent yields (69%-95%) in a shorter time than conventional approach. 4-Chlorophenyl moiety containing theophylline-1,2,4-triazole 4c displayed significantly higher inhibitory activity against HCV serine protease enzyme (IC = 0.015 ± 0.25 mg) in comparison to ribavirin (IC = 0.165 ± 0.053 mg), but showed excellent binding affinity (-7.55 kcal/mol) with the active site of serine protease, better than compound 4c (-6.90 kcal/mol) as well as indole-based control compound 5 (-7.42 kcal/mol). In terms of percentage inhibition of serine protease, 2-chlorophenyl compound 4b showed the maximum percentage inhibition (86%), more than that of the 3,4-dichlorophenyl compound 4c (76%) and ribavirin (81%). 3,4-Dimethylphenyl-based theophylline-1,2,4-triazole 4g showed the lowest minimum inhibitory concentration (MIC = 0.28 ± 0.50 μg/mL) against the bacterial strain as compared to the standard drug penicillin (MIC = 1 ± 1.50 μg/mL). The other 4-methylphenyl theophylline-1,2,4-triazole 4e (MIC = 0.20 ± 0.08 μg/mL) displayed the most potent antibacterial potential against in comparison to the standard drug penicillin (MIC = 2.4 ± 1.00 μg/mL). Molecular docking studies further helped in an extensive understanding of all of the interactions between compounds and the enzyme active site, and DFT studies were also employed to gain insights into the molecular structure of the synthesized compounds. The results indicated that theophylline-linked triazole derivatives 4b and 4c showed promise as leading contenders in the fight against the HCV virus. Moreover, compounds 4e and 4g demonstrated potential as effective chemotherapeutic agents against and , respectively. To substantiate these findings, additional studies and clinical trials are imperative, laying the groundwork for their integration into future drug design and development.
茶碱，一种含氮杂环化合物，是医学研究人员关注的焦点，他们致力于开发具有多种药理应用的衍生物。在这项工作中，我们提出了一种改进的合成方法，利用超声辅助合成方法制备一系列茶碱-1,2,4-三唑-S-连接的N-苯基乙酰胺（4a‒g）。目的是评估合成的茶碱-1,2,4-三唑（4a‒g）作为丙型肝炎病毒丝氨酸蛋白酶抑制剂以及针对QB-928和AB-274的抗菌剂的有效性。与传统方法相比，茶碱-1,2,4-三唑的产率良好至优异（69%-95%），且合成时间更短。含4-氯苯基的茶碱-1,2,4-三唑4c对丙型肝炎病毒丝氨酸蛋白酶的抑制活性（IC = 0.015 ± 0.25 mg）明显高于利巴韦林（IC = 0.165 ± 0.053 mg），但与丝氨酸蛋白酶活性位点的结合亲和力极佳（-7.55 kcal/mol），优于化合物4c（-6.90 kcal/mol）以及吲哚类对照化合物5（-7.42 kcal/mol）。就丝氨酸蛋白酶的抑制百分比而言，2-氯苯基化合物4b的抑制百分比最高（86%），高于3,4-二氯苯基化合物4c（76%）和利巴韦林（81%）。与标准药物青霉素（MIC = 1 ± 1.50 μg/mL）相比，基于3,4-二甲基苯基的茶碱-1,2,4-三唑4g对该细菌菌株的最低抑菌浓度最低（MIC = 0.28 ± 0.50 μg/mL）。另一种4-甲基苯基茶碱-1,2,4-三唑4e（MIC = 0.20 ± 0.08 μg/mL）对该菌的抗菌潜力最强，优于标准药物青霉素（MIC = 2.4 ± 1.00 μg/mL）。分子对接研究进一步有助于深入了解化合物与酶活性位点之间的所有相互作用，同时也采用了密度泛函理论（DFT）研究来深入了解合成化合物的分子结构。结果表明，茶碱连接的三唑衍生物4b和4c有望成为对抗丙型肝炎病毒的主要候选药物。此外，化合物4e和4g分别显示出作为针对该菌和该菌的有效化疗药物的潜力。为了证实这些发现，必须进行更多的研究和临床试验，为将它们整合到未来的药物设计和开发中奠定基础。
