title: Intermolecular interaction of voriconazole analogues with model membrane by DSC and NMR, and their antifungal activity using NMR based metabolic profiling.
abstract: The development of novel antifungal agents with high susceptibility and increased potency can be achieved by increasing their overall lipophilicity. To enhance the lipophilicity of voriconazole, a second generation azole antifungal agent, we have synthesized its carboxylic acid ester analogues, namely p-methoxybenzoate (Vpmb), toluate (Vtol), benzoate (Vbz) and p-nitrobenzoate (Vpnb). The intermolecular interactions of these analogues with model membrane have been investigated using nuclear magnetic resonance (NMR) and differential scanning calorimetric (DSC) techniques. The results indicate varying degree of changes in the membrane bilayer's structural architecture and physico-chemical characteristics which possibly can be correlated with the antifungal effects via fungal membrane. Rapid metabolite profiling of chemical entities using cell preparations is one of the most important steps in drug discovery. We have evaluated the effect of synthesized analogues on Candida albicans. The method involves real time (1)H NMR measurement of intact cells monitoring NMR signals from fungal metabolites which gives Metabolic End Point (MEP). This is then compared with Minimum Inhibitory Concentration (MIC) determined using conventional methods. Results indicate that one of the synthesized analogues, Vpmb shows reasonably good activity.
authors.affiliation: Prin K.M. Kundnani College of Pharmacy, Plot 23, Jyot Joy Building, Rambhau Salgaonkar Marg, Cuffe Parade, Mumbai 400005, India.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Kalamkar
authors.forename: Mamata
authors.initials: M
authors.lastname: Joshi
authors.forename: Varsha
authors.initials: V
authors.lastname: Borkar
authors.forename: Sudha
authors.initials: S
authors.lastname: Srivastava
authors.forename: Meena
authors.initials: M
authors.lastname: Kanyalkar
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002152:Calorimetry, Differential Scanning; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry; D004952:Esters; D062425:Hydroxybenzoate Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D055442:Metabolome; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D044366:Transition Temperature; D014230:Triazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D002264:Carboxylic Acids; D004952:Esters; D062425:Hydroxybenzoate Ethers; D008051:Lipid Bilayers; D011743:Pyrimidines; D014230:Triazoles; D015060:1,2-Dipalmitoylphosphatidylcholine; C004520:4-anisic acid; D065819:Voriconazole
keywords: Antifungal; DPPC; Differential scanning calorimeter (DSC); MEP; Nuclear magnetic resonance (NMR); Voriconazole