As previously reported azole class antifungal
As previously reported, azole class antifungal drugs inhibit fungal CYP450 14α-demethylase, as this interrupts the conversion of lanosterol to ergosterol, a component of the fungal cell membrane (Hof, 2006). Furthermore, correlation between fluconazole dose, the extent of hepatic hypertrophy, the levels of Cyp450 expression, and Cyp450 mediated enzymatic activities was also investigated (Lee et al., 2009). Here in, an elevation in Cyp450 in C. albicans intoxicated group was observed. Nevertheless, a significant down-regulation was apparent in mice treated with fluconazole, 13b and 14b. Besides, 13b and 14b high doses regimen considerably reversed the level of Cyp 450 back near to the normal value indicating hepatotoxic effect of fluconazole and demonstrated the efficiency of the new synthetic compounds 13b and 14b in regulation of Cyp 450 gene expression.
C. albicans has multiple factors that cause disease. These factors includes phenotypic switching, adherence and secreted hydrolyses. They are regulated by different genes, particularly the agglutinin-like sequence (ALS), secreted aspartyl proteinase, and lipase families which are involved in the pathogenesis and adhesion of C. albicans to mucosa and epithelial hiv protease (Hoyer et al., 2008). In the current study C. albicans infection caused a significant up-regulation in mRNA gene expression of ALS1 as compared to the control value. This finding was previously reported by Murciano et al., 2012 as an elevation in C. albicans ALS1 proteins expression in human oral epithelial cells. Moreover, a significant down regulation was demonstrated in all treated groups with the superiority of 14b high dose regimen.
Oxidative stress has been linked to intracellular MAP kinase signaling pathways which lead to up-regulation of COX-2 gene expression (Tago et al., 2001). In this concept, we investigated an elevation in vaginal COX-2 gene expression post C. albicans infection. Previously, it has been reported that COX-2 induction occurs following C. albicans infection (Lee et al., 2009). Moreover, modulation of COX-2 gene expression in all treated groups with the superiority of 14b high dose was observed. This finding indicated the efficiency of 14b as antifungal agent. It is well known that C. albicans ability to establish a persistent infection depends on signals that regulate release of factors from target cells responsible for replication of pathogen. This cell signaling is designed to serve the purpose of cell survival for both host and pathogen. Infection by C. albicans of host tissue and cells is mediated through surface receptors, such as mannose, glucan, integrins, etc. (Castro et al., 1996) and has been found to release pro inflammatory cytokines and large amount of arachidonic acid (AA) from host cells. AA is subsequently converted by lipoxygenases and cyclooxygenases (COXs) to eicosanoids (Noverr et al., 2001).
The antiinflammatory effect of pyridine derivativates has been previously reported via prostaglandin-2 reduction (Mohamed et al., 2010).
Naphthalene is important aryl ring in many active compounds such as anti-inflammatory, anti-bacterial, anti-microbial and anti-cancer. In recent trends, heterocycles plays a major role in drug synthesis (Sharma and Singh, 2006). Pyrazole derivatives have been the subject of substantial attention by synthetic and medicinal chemists due to their role in many biological activities such as anticancer, antiviral, anti-inflammatory, antifungal, antimicrobial, antihistaminic, antiplatelet and analgesic activities. The mechanism of action for this compounds is linked to the nonselective or selective inhibition of two cyclooxygenase isoform, COX-1 & COX-2 (Feixas and Jimenez, 2011)
Conclusion From the current investigation, it could be concluded that the combination of pyridine and Naphthalene derivatives (principally 14b in a high dose) could be used as a novel antifungal agents to treat important fungal infections caused by C. albicans. So it is recommended to be improved and evaluated as a novel antifungal drug with less effect on liver function and able to overcome the emergence of the resistance problem.