The acridones, new inhibitors of mitochondrial NADH: ubiquinone oxidoreductase (complex I).

Acridones (9-azaanthracen-10-ones) were found to be powerful inhibitors of mitochondrial NADH: ubiquinone oxidoreductase. Their inhibitory activity was best if an alkyl or alkyloxy substituent resided in the 4-position. Biological activity reached a maximum at a chain length of 9-10 A. Halogen substitution in position 7, but not in positions 6 and 7, further enhanced activity. 2-Alkylacridones were much less active. Inhibitory activity in a Quantitative Structure-Activity Relationship (QSAR) could be correlated to Verloop's STERIMOL parameters L and L2 (Verloop, A., Hoogenstraten, W. and Tipker, J. (1976) in Drug Design (Ariens, E.J., ed.), Vol. 7, pp. 165-207, Academic Press, New York). The QSAR could be further improved by inclusion of the lipophilicity parameter pi.