Rational design of N-alkyl derivatives of 2-amino-2-deoxy- d-glucitol-6P as antifungal agents

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 23; pp. 6602 - 6606
• Main Authors: Melcer, Anna, Łącka, Izabela, Gabriel, Iwona, Wojciechowski, Marek, Liberek, Beata, Wiśniewski, Andrzej, Milewski, Sławomir
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2007; Elsevier
• Subjects: Aminoglucitol derivatives; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Antifungals; Biological and medical sciences; Candida albicans - drug effects; Candida albicans - enzymology; Candida albicans - growth & development; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Glucosamine - analogs & derivatives; Glucosamine - chemical synthesis; Glucosamine - pharmacology; Glucosamine-6-phosphate synthase; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - antagonists & inhibitors; Humans; Medical sciences; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - growth & development; Antifungals; Aminoglucitol derivatives; Glucosamine-6-phosphate synthase; Ascomycota; Enzyme; Transferases; Enzyme inhibitor; In vitro; Biological activity; Glutamine-fructose-6-phosphate transaminase (isomerizing); Fungi; Glucosamine-6-p- hosphate synthase; Alditol; Antifungal agent; Transaminases; Candida; Fungi Imperfecti; Chemical synthesis; Saccharomyces cerevisiae
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.09.072

N-Alkylation of d-glucosaminitol-6P affords compounds that inhibit Candida albicans glucosamine-6P synthase and exhibit antifungal activity (MIC = 0.08 − 0.625 mg mL −1). N-Alkyl and N, N-dialkyl derivatives of 2-amino-2-deoxy- d-glucitol-6P (ADGP) were synthesized and found to inhibit growth of human pathogenic fungi (MICs in the 0.08–0.625 mg mL −1 range for the most active compounds). It was thus shown that N-alkylation of ADGP provides novel inhibitors of a fungal enzyme, glucosamine-6P synthase, exhibiting higher antifungal activity than the parent compound, due to the increased lipophilicity and better uptake by fungal cells.