Abstract
Clotrimazole (1-[(2-chlorophenyl)-diphenylmethyl]-imidazole) is an azole antifungal drug belonging to the imidazole subclass that is widely used in pharmacology and that can be incorporated in membranes. We studied its interaction with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) phospholipid vesicles by using differential scanning calorimetry and found that the transition temperature decreases progressively as the concentration of clotrimazole increases. However, the temperature of completion of the transition remained constant despite the increase of clotrimazole concentration, suggesting the formation of fluid immiscibility. 1H-NMR and 1H NOESY MAS-NMR were employed to investigate the location of clotrimazole in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) phospholipid membranes. In the presence of clotrimazole, all the resonances originating from POPC were shifted upfield, but mainly those corresponding to C2 and C3 of the fatty acyl, chains suggesting that clotrimazole aromatic rings preferentially locate near these carbons. In the same way, 2D-NOESY measurements showed that the highest cross-relaxation rates between protons of clotrimazole and POPC were with those bound to the C2 and C3 carbons of the fatty acyl chains. Molecular dynamics simulations indicated that clotrimazole is located near the top of the hydrocarbon-chain phase, with the nitrogen atoms of the imidazole ring of clotrimazole being closest to the polar group of the carbonyl moiety. These results are in close agreement with the NMR and the conclusion is that clotrimazole is located near the water–lipid interface and in the upper part of the hydrophobic bilayer.
Highlights
Clotrimazole (1-[(2-chlorophenyl)-diphenylmethyl]-imidazole) is an azole antifungal drug belonging to the imidazole subclass with a molecular weight of 344.8 g/mol
It is possible to observe a considerable influence of clotrimazole both on the pre-transition, indicative of the transition from the gel (Lβ’ ) to ripple (Pβ’ ) phase, and on the gel to liquid-crystalline phase transition of DMPC
Clotrimazol is a lipophilic compound used as an antifungal drug that is incorporated into membranes, where it may interfere with the activity of membrane enzymes, such as SERCA ATPases [5,6,7]
Summary
Clotrimazole (1-[(2-chlorophenyl)-diphenylmethyl]-imidazole) is an azole antifungal drug belonging to the imidazole subclass with a molecular weight of 344.8 g/mol.The clotrimazole molecule consists of a quaternary carbon substituted with an imidazole group, two phenyl rings and a phenyl ring with a chloro-substitution at the ortho-position.Its spatial conformation is tetrahedral (Figure 1).Its principal medicinal use is for the treatment of vaginal and oral candidiasis [1,2]and athlete’s foot [3], caused by Candida albicans and different fungi, respectively, it is used for infections caused by other fungi. Clotrimazole (1-[(2-chlorophenyl)-diphenylmethyl]-imidazole) is an azole antifungal drug belonging to the imidazole subclass with a molecular weight of 344.8 g/mol. The clotrimazole molecule consists of a quaternary carbon substituted with an imidazole group, two phenyl rings and a phenyl ring with a chloro-substitution at the ortho-position. Its spatial conformation is tetrahedral (Figure 1). Its mechanism of action involves the inhibition of Cyp51p (cytochrome P450 14alpha-demethylase), which causes the demethylation of 14-α-lanosterol, Cyp51p. This enzyme is involved in the synthesis of ergosterol, which is the major component of fungal cytoplasmic membranes. Blocking the ergosterol synthesis pathway leads to the accumulation of 14-α-methylated sterols, resulting in a structural and functional defect of the membrane [4]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
