Potent Antifungal Synergy of Phthalazinone and Isoquinolones with Azoles Against Candida albicans

Abstract

Four phthalazinones (CIDs 22334057, 22333974, 22334032, 22334012) and one isoquinolone (CID 5224943) were previously shown to be potent enhancers of antifungal activity of fluconazole against Candida albicans. Several even more potent analogues of these compounds were identified, some with EC 50 as low as 1 nM, against C. albicans. The compounds exhibited pharmacological synergy (FIC < 0.5) with fluconazole. The compounds were also shown to enhance the antifungal activity of isavuconazole, a recently FDA approved azole antifungal. Isoquinolone 15 and phthalazinone 24 were shown to be active against several resistant clinical isolates of C. albicans. KEYWORDS: Candida albicans, antifungal agents, fluconazole, synergy, phthalazinone, isoquinolone A zoles continue to be the drug of choice for many types of invasive fungal infections, acting on a key enzyme, sterol 14α-demethylase, in the ergosterol biosynthesis pathway. The azole family of antifungals has evolved continuously since the initial introduction of ketoconazole in the 1980s 1 with the goal of achieving high affinity toward the fungal P450 14α-demethylase, low affinity toward human CYP enzymes, 2,3 and, more recently, evasion of fungal resistance mechanisms. 4 Fluconazole, introduced in 1990, proved well-tolerated in patients and has been used ubiquitously to treat invasive candidiasis. 1 The emergence of fluconazole resistance has led to the increasing use of echinocandins and the development of third-generation azoles (voriconazole, posoconazole, isavuconazole) with higher affinity. 5 Of the third-generation drugs, posoconazole and voriconazole work against a broader range of fungal pathogens but are more expensive and have other disadvantages: posoconazole has a less flexible dosing and absorption profile than fluconazole; voriconazole may be ineffective against strains that have already developed resistance toward fluconazole. 6 Newer azole drugs like albaconazole and fosravuconazole are still in development.The development of improved azoles has been paralleled by the search for small molecules that enhance the antifungal effect of existing azoles, 7−10 but the efforts have been met with limited success. 11,12 A wide range of azole enhancers have been shown to exhibit antifungal synergy; 13 two approved drugs, flucytosine 14 and calcineurin inhibitors, 15−19 have been shown to synergize with fluconazole against at low concentrations (<10 μg/mL) against strains of C. albicans but have limitations for general use. Against other species, 20 flucytosine instead antagonizes the effect of fluconazole, so the benefits of flucytosine-azole combinations are not clear. 21 Calcineurin inhibitors such as sirolimus and tacrolimus depend on human CYP enzymes for metabolic clearance; azole drugs like fluconazole exert off-target effects on these human CYP enzymes. Buildup of these calcineurin inhibitors in plasma increases risk of nephrotoxicity and, as immunosuppressants, may increase rates of infection from other pathogenic fungal species. 22−24 Giv...

Expeditious Synthesis of Isoquinolone Derivatives by Rhodium(I)-Catalyzed Annulation Reaction through C–C Bond Cleavage

“…As structural motifs widely found in diverse natural products, isoquinolones play important roles in pharmaceutical chemistry. Compounds containing the isoquinolone skeleton are famous for their antitumor, antiallergic, and antipsychotic activities . Consequently, great efforts of synthetic chemists have been devoted to establishing some efficient procedures for the preparation of isoquinolone derivatives in recent years. − Among these, the most amazing and popular strategy is the transition-metal-catalyzed oxidative annulation of benzamide derivatives with alkynes through C–H/N–H dual activation. , Several hypervalent transition-metal catalysts, such as Rh III , Ru II , Co III , Pd II , and Fe III , can be employed in this transformation (Figure ).…”

Identification of Some Promising Heterocycles Useful in Treatment of Allergic Rhinitis: Virtual Screening, Pharmacophore Mapping, Molecular Docking, and Molecular Dynamics

“…Library generation and SwissADME profiling. The one hundred eighty-four compounds [ 16 – 18 ] were classified into three main clusters using the online SwissADME tool [ 19 – 21 ], as shown in Fig. 3.…”

Pharmacological activities of various phthalazine and phthalazinone derivatives

“…The compounds were also shown to enhance the antifungal activity of isavuconazole, an antifungal. Phthalazinone were shown to be active against several resistant clinical isolates of C. albicans (Mood et al, 2017).…”