SCHEDULED MAINTENANCE
New 8-hydroxyquinoline derivatives highlight the potential of this class for treatment of fungal infections†
*ab
Maycon Antonio
de Cesare,
ab
Alexandre Meneghello
Fuentefria
bc
and
Saulo Fernandes
de Andrade
*abc
Abstract
The oral administration of clioquinol – a potent 8-hydroxyquinoline antimicrobial drug – was forbidden due to suspicion of it being the cause of SMON (subacute myelo-optic-neuropathy) in Japan. However, this adverse effect was only observed in Japan, despite the fact that the drug was used worldwide. In addition, studies have shown that vitamin B12 deficiency could be involved in this process. Thus, the interest in the modification of this compound has recently emerged as a strategy to find new drug candidates. In the present work, we have designed and synthesized a novel series of clioquinol derivatives by the modification of the 7-position of this compound. Twenty-one derivatives were prepared from commercially available clioquinol in two or three steps: 8-OH-protection of clioquinol followed by the palladium-catalyzed cross-coupling reaction to introduce the arylamine group at position 7 resulting in derivatives 4a–4j. Finally, deprotection of the hydroxyl group gave derivatives 5a–5i and 10a–10b. The compounds prepared were tested against Candida spp. and dermatophyte isolates by the broth microdilution method. We have found a clear structure–activity relationship. The presence of free hydroxyl in the 8-position and the introduction of the hydrophilic heterocyclic substituent at the 7-position are important for the antifungal activity of this class. Moreover, the introduction of dimethoxy groups at the pyrimidinyl ring attached to the 7-position seems to be promising against dermatophytes and Candida albicans. Among all derivatives, compound 5h presented interesting activity against all fungal species tested (with MIC values of 4 μg mL−1), along with low toxicity in normal cells. This derivative is non-irritant with the absence of topical toxicity. In addition, 5h does not seem to act as an ionophore in fungal cells, similarly to clioquinol. These compounds appear to have a scavenger effect, which suggests their selectivity for fungal cells. Taken together, these findings indicate the potential of 5h to be developed as an antifungal agent.
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