Novel Galactopyranoside Esters: Synthesis, Mechanism, In Vitro Antimicrobial Evaluation and Molecular Docking Studies

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-06, Vol.27 (13), p.4125
• Main Authors: Matin, Priyanka, Hanee, Umme, Alam, Muhammad Shaiful, Jeong, Jae Eon, Matin, Mohammed Mahbubul, Rahman, Md Rezaur, Mahmud, Shafi, Alshahrani, Mohammed Merae, Kim, Bonglee
• Format: Article
• Language: English
• Subjects: ADMET studies; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antibacterial agents; antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antimicrobial agents; Antiviral agents; Binding energy; Bioavailability; Carbohydrates; COVID-19; dynamics simulation; Esters; Esters - chemistry; Fluconazole; Fungicides; Galactose; Humans; Metabolism; methyl α-D-galactopyranoside esters; Molecular docking; Molecular Docking Simulation; one-step acylation; Pathogens; Pharmacokinetics; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Thermodynamics; Toxicity
• ISSN: 1420-3049; 1420-3049
• 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.