| We have prepared a series of pyridazinone derivatives, starting with dichloropyridazinone (37, 133 and 134), available from mucochloric acid. Due to their easy nucleophilic substitution and their biological activity, they were used as starting materials for the further synthesis of several 3(2H)-pyridazinone derivatives.; We have investigated antifungal properties of some known derivatives with the agar dilution method, which showed that 134 and 397 display a broad spectrum of activity against all the fungi tested, but 134 was the most active of this series against Candida albicans and Cryptococcus neoformans, and much more active than amphotericin B and Ketoconazole, particularly against Trichophyton rubrum and Trichophyton mentagraphytes, the two major ethiological agents of dermatomycoses. This compound also proved to be a moderate inhibitor of (1,3)-beta-D-glucan synthase, a catalyst of one of the major polymers of the fungal cell wall, without any inhibitory activity against chitin synthase. Significant activities were also shown by other of these derivatives against dermatophytes, which is a contribution to the development of antifungal drugs. The best activity was observed in the presence of a 6-nitro group and/or halo atoms in the positions of the ring as in 134 and 397.; The lipophilicities of several pyridazinone derivatives were described by the log Pexptl values determined experimentally with the standard shaking flask method, which revealed a higher lipophilicity of the 4-isomer than of the 5-isomer, which is in agreement with our previously published results, and confirmed that not only the type, but also the position of the substituent plays a significant role in the lipophilicity of the pyridazinone derivatives. log P calculated by methods based on quantum-chemical approaches, such as ScilogPultra, could reproduce the higher lipophilicity of the 4-isomer, while Qlog P and Ghose could not distinguish the regioisomers at all; Villar and 3DNET reproduced the observed log P. The log P values calculated with the KOWWIN program were very different from the experimentally determined log P data. (Abstract shortened by UMI.)... |
