The role of amphotericin B amino group basicity in its antifungal action. A theoretical approach.

The role of basicity of the amine group of amphotericin B in the molecular mechanism of antifungal activity of this antibiotic has been investigated by AM1 and MNDO quantum chemistry methods. Calculations of proton affinity of the amine group, as a measure of its basicity, for appropriate models of free amphotericin B and its N-alkyl derivatives were carried out. These studies were preceded by a critical examination of the usefulness and reliability of both methods to predict the proton affinities of several aliphatic amines. It has been concluded that the diminution of protonability of the substituted amine group of amphotericin B correlates with the decrease of antifungal activity of the appropriate derivatives of antibiotic. It was experimentally demonstrated (A. Czerwiński et al., J. Antibiot. 44 (1991) 979) that the introduction of additional amine groups in such a derivative restores antifungal activity of the compound. In our studies it was evidenced, using theoretical methods, that the proton affinity of this additional amine group is similar to that in free amphotericin B.