THE ROLE OF AMPHOTERICIN-B AMINE GROUP BASICITY IN ITS ANTIFUNGAL ACTION - A THEORETICAL APPROACH

The role of basicity of the amine group of amphotericin B in the molec ular mechanism of antifungal activity of this antibiotic has been inve stigated by AMI and MNDO quantum chemistry methods. Calculations of pr oton affinity of the amine group, as a measure of its basicity, for ap propriate models of free amphotericin B and its N-alkyl derivatives we re carried out. These studies were preceded by a critical examination of the usefulness and reliability of both methods to predict the proto n affinities of several aliphatic amines. It has been concluded that t he diminution of protonability of the substituted amine group of ampho tericin B correlates with the decrease of antifungal activity of the a ppropriate derivatives of antibiotic. It was experimentally demonstrat ed (A. Czerwinski et at, J. Antibiot. 44 (1991) 979) that the introduc tion of additional amine groups in such a derivative restores antifung al activity of the compound. In our studies it was evidenced, using th eoretical methods, that the proton affinity of this additional amine g roup is similar to that in free amphotericin B.