Matin Mohammed M, Chakraborty Priyanka, Alam Muhammad S, Islam Mohammad M, Hanee Umme
Bioorganic and Medicinal Chemistry Laboratory, Department of Chemistry, Faculty of Science, University of Chittagong, Chattogram, 4331, Bangladesh.
Bioorganic and Medicinal Chemistry Laboratory, Department of Chemistry, Faculty of Science, University of Chittagong, Chattogram, 4331, Bangladesh.
Carbohydr Res. 2020 Oct;496:108130. doi: 10.1016/j.carres.2020.108130. Epub 2020 Aug 14.
Direct unimolar one-step valeroylation of methyl α-d-mannopyranoside (MDM) furnished mainly 6-O-valeroate. However, similar reaction catalyzed by DMAP resulted 3,6-di-O-valeroate (21%) and 6-O-valeroate (47%) indicating reactivity sequence as 6-OH>3-OH>2-OH,4-OH. To get potential antimicrobial agents, 6-O-valeroate was converted into four 2,3,4-di-O-acyl esters, and 3,6-di-O-valeroate was converted into 2,4-di-O-acetate. Direct tetra-O-valeroylation of MDM gave a mixture of 2,3,4,6-tetra-O-valeroate and 2,3,6-tri-O-valeroate indicating that the C2-OH is more reactive than the equatorial C4-OH. The activity spectra analysis along with in vitro antimicrobial evaluation clearly indicated that these novel MDM esters had better antifungal activities over antibacterial agents. In this connection, molecular docking indicated that these MDM esters acted as competitive inhibitors of sterol 14α-demethylase (CYP51), an essential enzyme for clinical target to cure several infectious diseases. Furthermore, pharmacokinetic studies revealed that these MDM esters may be worth considering as potent candidates for oral and topical administration. Structure activity relationship (SAR) affirmed that saturated valeric chain (C5) in combination with caprylic (C8) chains was more promising CYP51 inhibitor over conventional antifungal antibiotics.
α-D-吡喃甘露糖苷（MDM）的直接单分子一步戊酰化主要生成6-O-戊酸酯。然而，由4-二甲氨基吡啶（DMAP）催化的类似反应生成了3,6-二-O-戊酸酯（21%）和6-O-戊酸酯（47%），表明反应活性顺序为6-OH>3-OH>2-OH,4-OH。为了获得潜在的抗菌剂，6-O-戊酸酯被转化为四种2,3,4-二-O-酰基酯，3,6-二-O-戊酸酯被转化为2,4-二-O-乙酸酯。MDM的直接四-O-戊酰化得到了2,3,4,6-四-O-戊酸酯和2,3,6-三-O-戊酸酯的混合物，这表明C2-OH比赤道面的C4-OH更具反应活性。活性谱分析以及体外抗菌评估清楚地表明，这些新型MDM酯比抗菌剂具有更好的抗真菌活性。在这方面，分子对接表明这些MDM酯作为甾醇14α-脱甲基酶（CYP51）的竞争性抑制剂，CYP51是治疗几种传染病的临床靶点的必需酶。此外，药代动力学研究表明，这些MDM酯可能值得作为口服和局部给药的有力候选物加以考虑。构效关系（SAR）证实，与辛酸（C8）链结合的饱和戊酸链（C5）比传统抗真菌抗生素更有希望成为CYP51抑制剂。
