Bioorganic and Medicinal Chemistry Laboratory, Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh.
Department of Pharmacy, University of Science and Technology Chittagong, Chittagong 4202, Bangladesh.
Molecules. 2022 Jun 27;27(13):4125. doi: 10.3390/molecules27134125.
One-step direct unimolar valeroylation of methyl α-D-galactopyranoside (MDG) mainly furnished the corresponding 6-O-valeroate. However, DMAP catalyzed a similar reaction that produced 2,6-di-O-valeroate and 6-O-valeroate, with the reactivity sequence as 6-OH > 2-OH > 3-OH,4-OH. To obtain novel antimicrobial agents, 6-O- and 2,6-di-O-valeroate were converted into several 2,3,4-tri-O- and 3,4-di-O-acyl esters, respectively, with other acylating agents in good yields. The PASS activity spectra along with in vitro antimicrobial evaluation clearly indicated that these MDG esters had better antifungal activities than antibacterial agents. To rationalize higher antifungal potentiality, molecular docking was conducted with sterol 14α-demethylase (PDB ID: 4UYL, Aspergillus fumigatus), which clearly supported the in vitro antifungal results. In particular, MDG ester 7−12 showed higher binding energy than the antifungal drug, fluconazole. Additionally, these compounds were found to have more promising binding energy with the SARS-CoV-2 main protease (6LU7) than tetracycline, fluconazole, and native inhibitor N3. Detailed investigation of Ki values, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and the drug-likeness profile indicated that most of these compounds satisfy the drug-likeness evaluation, bioavailability, and safety tests, and hence, these synthetic novel MDG esters could be new antifungal and antiviral drugs.
一步法直接单摩尔丙酰化甲基 α-D-吡喃半乳糖苷（MDG）主要生成相应的 6-O-丙酰化物。然而，DMAP 催化的类似反应产生 2,6-二-O-丙酰化物和 6-O-丙酰化物，反应性顺序为 6-OH > 2-OH > 3-OH，4-OH。为了获得新型抗菌剂，6-O-和 2,6-二-O-丙酰化物分别与其他酰化剂在良好的产率下转化为几种 2,3,4-三-O-和 3,4-二-O-酰酯。PASS 活性谱以及体外抗菌评价清楚地表明，这些 MDG 酯类具有比抗菌药物更好的抗真菌活性。为了合理化更高的抗真菌潜力，用甾醇 14α-脱甲基酶（PDB ID：4UYL，烟曲霉）进行了分子对接，这清楚地支持了体外抗真菌结果。特别是，MDG 酯 7-12 与抗真菌药物氟康唑相比具有更高的结合能。此外，与四环素、氟康唑和天然抑制剂 N3 相比，这些化合物与 SARS-CoV-2 主要蛋白酶（6LU7）的结合能更有前途。详细的 Ki 值、吸收、分布、代谢、排泄和毒性（ADMET）以及药物相似性分析表明，这些化合物中的大多数满足药物相似性评价、生物利用度和安全性测试，因此，这些合成的新型 MDG 酯类可能是新型抗真菌和抗病毒药物。
