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.

中文翻译：

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克霉唑使磷脂膜流化并定位于膜极性部分附近的疏水部分

克霉唑 (1-[(2-chlorophenyl)-diphenylmethyl]-imidazole) 是一种唑类抗真菌药物，属于咪唑亚类，广泛用于药理学，可掺入膜中。我们通过差示扫描量热法研究了它与 1,2-二肉豆蔻酰-sn-甘油-3-磷酸胆碱 (DMPC) 磷脂囊泡的相互作用，发现随着克霉唑浓度的增加，转变温度逐渐降低。然而，尽管克霉唑浓度增加，转变完成的温度保持恒定，表明形成了流体不混溶性。¹ H-NMR 和¹H NOESY MAS-NMR 用于研究克霉唑在 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) 磷脂膜中的位置。在克霉唑存在的情况下，所有源自 POPC 的共振都向高场移动，但主要是对应于脂肪酰基的 C2 和 C3 的那些，表明克霉唑芳环优先位于这些碳附近。同样，2D-NOESY 测量表明，克霉唑和 POPC 的质子之间的交叉弛豫率最高的是与脂肪酰基链的 C2 和 C3 碳结合的质子。分子动力学模拟表明，克霉唑位于烃链相顶部附近，克霉唑咪唑环的氮原子最接近羰基部分的极性基团。