Kawsar Sarkar M A, Al-Mijalli Samiah Hamad, Bouzid Gassoumi, Abdallah Emad M, Siddiquee Noimul H, Hosen Mohammed A, Horchani Mabrouk, Ghalla Houcine, B Jannet Hichem, Fujii Yuki, Ozeki Yasuhiro
Laboratory of Carbohydrate and Nucleoside Chemistry, Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh.
Department of Biology, College of Sciences, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
Pharmaceuticals (Basel). 2025 May 27;18(6):806. doi: 10.3390/ph18060806.
Nucleoside precursors and derivatives play pivotal roles in the development of antimicrobial and antiviral therapeutics. The 2022 global outbreak of monkeypox (Mpox) across more than 100 nonendemic countries underscores the urgent need for novel antiviral agents. This study aimed to synthesize and evaluate a series of 5'--(palmitoyl) derivatives (compounds -), incorporating various aliphatic and aromatic acyl groups, for their potential antimicrobial activities. The structures of the synthesized derivatives were confirmed through physicochemical, elemental, and spectroscopic techniques. In vitro antibacterial efficacy was assessed, including minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) determinations for the most active compounds ( and ). The antifungal activity was evaluated based on mycelial growth inhibition. Density functional theory (DFT) calculations were employed to investigate the electronic and structural properties, including the global reactivity, frontier molecular orbital (FMO), natural bond orbital (NBO), and molecular electrostatic potential (MEP). Molecular docking studies were conducted against the monkeypox virus and the Marburg virus. The top-performing compounds (, , and ) were further evaluated via 200 ns molecular dynamics (MD) simulations. ADMET predictions were performed to assess drug-likeness and pharmacokinetic properties. Compounds and demonstrated remarkable antibacterial activity compared with the precursor molecule, while most derivatives inhibited fungal mycelial growth by up to 79%. Structure-activity relationship (SAR) analysis highlighted the enhanced antibacterial/antifungal efficacy with CH(CH)CO- and CH(CH)CO-acyl chains. In silico docking revealed that compounds , , and had higher binding affinities than the other derivatives. MD simulations confirmed the stability of the protein-ligand complexes. ADMET analyses revealed favorable drug-like profiles for all the lead compounds. The synthesized compounds , , and exhibit promising antimicrobial and antiviral activities. Supported by both in vitro assays and comprehensive in silico analyses, these derivatives have emerged as potential candidates for the development of novel therapeutics against bacterial, fungal, and viral infections, including monkeypox and Marburg viruses.
核苷前体和衍生物在抗菌和抗病毒治疗药物的开发中发挥着关键作用。2022年猴痘在100多个非流行国家的全球爆发凸显了对新型抗病毒药物的迫切需求。本研究旨在合成并评估一系列5'-（棕榈酰基）衍生物（化合物-），这些衍生物含有各种脂肪族和芳香族酰基，以考察其潜在的抗菌活性。通过物理化学、元素分析和光谱技术确认了合成衍生物的结构。评估了体外抗菌效果，包括对活性最强的化合物（和）进行最低抑菌浓度（MIC）和最低杀菌浓度（MBC）测定。基于菌丝生长抑制评估了抗真菌活性。采用密度泛函理论（DFT）计算来研究电子和结构性质，包括全局反应性、前线分子轨道（FMO）、自然键轨道（NBO）和分子静电势（MEP）。针对猴痘病毒和马尔堡病毒进行了分子对接研究。通过200 ns分子动力学（MD）模拟进一步评估了表现最佳的化合物（、和）。进行了ADMET预测以评估药物相似性和药代动力学性质。与前体分子相比，化合物和表现出显著的抗菌活性，而大多数衍生物对真菌菌丝生长的抑制率高达79%。构效关系（SAR）分析强调了带有CH(CH)CO-和CH(CH)CO-酰基链的衍生物具有增强的抗菌/抗真菌功效。计算机模拟对接显示化合物、和比其他衍生物具有更高的结合亲和力。MD模拟证实了蛋白质-配体复合物的稳定性。ADMET分析表明所有先导化合物都具有良好的药物相似性特征。合成的化合物、和展现出有前景的抗菌和抗病毒活性。在体外试验和全面的计算机模拟分析的支持下，这些衍生物已成为开发针对细菌、真菌和病毒感染（包括猴痘和马尔堡病毒）的新型治疗药物的潜在候选物。
