8-Hydroxyquinoline 1,2,3-triazole derivatives with promising and selective antifungal activity

Abstract

Fungal infections that affect humans and plants have increased significantly in recent decades. However, these pathogens are still neglected when compared to other infectious agents. Due to the high prevalence of these infections, the need for new molecules with antifungal potential is recognized, as pathogenic species are developing resistance to the main drugs available. This work reports the design and synthesis of 1,2,3-triazole derivatives of 8-hydroxyquinoline, as well as the determination of their activities against a panel of fungal species: Candida spp., Trichosporon asahii, Magnusiomyces capitatus, Microsporum spp., Trichophyton spp. and Fusarium spp. The triazoles 5-(4-phenyl-1H-1,2,3-triazol-1-yl)quinolin-8-ol (12) and 5-(4-(cyclohex-1-en-1-yl)-1H-1,2,3-triazol-1-yl)quinolin-8-ol (16) were more promising, presenting minimum inhibitory concentration (MIC) values between 1–16 µg/ml for yeast and 2–4 µg/ml for dermatophytes. However, no relevant anti-Fusarium spp. activity was observed. In the time-kill assays with Microsporum canis, 12 and 16 presented time-dependent fungicide profile at 96 h and 120 h in all evaluated concentrations, respectively. For Candida guilliermondii, 12 was fungicidal at all concentrations at 6 h and 16 exhibited a predominantly fungistatic profile. Both 12 and 16 presented low leukocyte toxicity at 4 µg/ml and the cell viability was close to 100% after the treatment with 12 at all tested concentrations. The sorbitol assay combined with SEM suggest that damages on the fungal cell wall could be involved in the activity of these derivatives. Given the good results obtained with this series, scaffold 4-(cycloalkenyl or phenyl)-5-triazol-8-hydroxyquinoline appears to be a potential pharmacophore for exploration in the development of new antifungal agents.

Novel Antimicrobial 8-Hydroxyquinoline-Based Agents: Current Development, Structure–Activity Relationships, and Perspectives

“…In addition, these derivatives have presented good results in biofilm dispersion assay, highlighting compound 14b, whose EC 50 was 2.09 and 3.26 μM for biofilms of S. aureus and S. epidermidis, respectively. 90 It is possible that ester compounds can act as prodrugs, considering their lability, as reported by Silva et al 60 Indeed, the anti-S. aureus activity of 14a and 14d is modulated by divalent ions, since there was a reduction in the antibacterial effect in the presence of Fe 2+ , and an increase in the activity in the presence of Zn 2+ , which was not observed when methicillin, erythromycin, or vancomycin were tested with metals. 91 This suggests a possible involvement of the 8-hydroxy and the nitrogen of the quinoline ring in a chelating effect, which is reported for many 8HQ derivatives.…”

“…Much like the sulfonamide derivatives, triazoles substituted by cycles ( 4a – d ) are promising, and compounds 4a – b also seem to affect the fungal cell wall. In addition, derivative 4b has shown low toxicity in leucocytes, even in high concentrations …”

“…Despite the modest antifungal activity, derivative 8a has shown synergistic effect with fluconazole against C. glabrata , in addition to inhibiting the proteinase secretion in C. albicans . , Moreover, fungi treated with 8a have presented reduced ergosterol content and morphological changes in cells, which suggests the fungal cellular membrane is an important target of this compound . Interestingly, the position of the substituent appears to affect the mechanism of antifungal action of triazole-containing 8HQs, since the compounds 4a – b (Figure ) with 5-triazoles possibly target the fungal cell wall and do not act on the fungal cellular membrane …”

“…In addition, derivative 4b has shown low toxicity in leucocytes, even in high concentrations. 60 The diazenyl group is useful for promoting coupling between two pharmacophoric cores, in addition to being present in compounds with antimicrobial activity. 61 8HQ derivatives containing a diazenyl group at position 5, linked to substituted phenyl (5a−i) or heterocycles (5j−l) (Figure 5) presented antibacterial and antifungal activities ranging from 74.99 to >1000 μM, 62−67 with the exception of derivative 5l.…”

“…75 Interestingly, the position of the substituent appears to affect the mechanism of antifungal action of triazole-containing 8HQs, since the compounds 4a−b (Figure 4) with 5-triazoles possibly target the fungal cell wall and do not act on the fungal cellular membrane. 60 The replacement of the triazole nucleus by the oxadiazole ring (9a−d, Figure 9) appears to reduce the antifungal effect, but the addition of a triazine group directly to 8-OH of 8HQ (10a−i, Figure 10) maintains the antifungal activity in general. 76−78 Some triazine derivatives were promising against C. albicans (10c) and Aspergillus sp.…”