Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans

Abstract

A spiroindolinone (1S,3R,3aR,6aS)-1-benzyl-6′-chloro-5-(4-fluorophenyl)-7′-methylspiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3′-1H-indole]-2′,4,6-trione was previously reported to enhance the antifungal effect of fluconazole against C. albicans. A diastereomer of that compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo-1, enhanced the effect of fluconazole with EC50 of 300 pM against a susceptible strain of C. albicans and as low as 2 nM against some resistant strains. Synazo-1 exhibits true synergy with fluconazole with an FIC index below 0.5 in the strains tested. Synazo-1 exhibited low toxicity in mammalian cells relative to the concentrations required for the antifungal synergy.

A Facile One-Pot Construction of Succinimide-Fused Spiro[Pyrrolidine-2,3′-Oxindoles] via 1,3-Dipolar Cycloaddition Involving 3-Amino Oxindoles and Maleimides

“…The spiro[pyrrolidine-2,3′-oxindole] has been identified as the core structural skeleton in some unnatural compounds with diverse biological activities [ 1 , 2 , 3 , 4 , 5 , 6 ]. As a subset of spiro[pyrrolidine-2,3′-oxindole], succinimide-fused spiro-[pyrrolidine-2,3′-oxindole] has been attracting more attention due to the recent discovery of some important biological activities such as anti-tumor [ 7 ], Ape1 inhibitor [ 8 ], and anti-fungal synergizer [ 9 ] ( Figure 1 ). As a consequence, much more attention has been paid to developing synthetic strategies toward the construction of this spirocyclic structure [ 2 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…As a subset of spiro[pyrrolidine-2,3′-oxindole], succinimide-fused spiro-[pyrrolidine-2,3′-oxindole] has been attracting more attention due to the recent discovery of some important biological activities such as anti-tumor [ 7 ], Ape1 inhibitor [ 8 ], and anti-fungal synergizer [ 9 ] ( Figure 1 ). As a consequence, much more attention has been paid to developing synthetic strategies toward the construction of this spirocyclic structure [ 2 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Among these reported approaches, most studies have focused on 1,3-dipolar cycloaddition of azomethine ylides generated in situ via decarboxylative condensation of isatins with amino acids ( Scheme 1 a) [ 7 , 9 , 13 , 14 , 15 ].…”

Synthesis of Functionalized 3-Spiro[cyclopropa[a]pyrrolizine]- and 3-Spiro[3-azabicyclo[3.1.0]hexane]oxindoles from Cyclopropenes and Azomethine Ylides via [3 + 2]-Cycloaddition

“…For example, coerulescine ( I ), horsfiline ( II ), and elacomine ( III ) are inhibitors of the mammalian cell cycle at the G2/M interphase, and spirotryprostatin A ( IV ) also showed anticancer activity . Various biological activities have been found for synthetic spiro-pyrrolidinyl oxindoles, e.g., anti-inflammatory, antidiabetic, antitumoric, antiviral, antimalarial, antifungal, antitubercular, and acetyl­cholinesterase (AChE) inhibitory properties …”

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

“…Following up on another hit from the Lindquist−Schreiber screen, we recently reported an analogue called synazo-1 that could enhance the antifungal effect of fluconazole with an EC 50 of 300 pM. 29 Encouraged by the discovery of potent fluconazole synergizers we set out to identify new lead compounds, optimize their structures, study their synergy with other azoles, and assess their selectivity for C. albicans.Among the compounds initially screened by Lindquist and coworkers were 233 structurally related N-arylphthalazinones (X = N, Figure 1) and N-arylisoquinolones (X = CH). Four phthalazinones and one isoquinolone were active in the initial screen.…”

“…Three of those compounds ,, were selected for further optimization, but none of the resulting compounds (ML189, ML212, and ML229) were active below 0.7 μM against CaCi-8. Following up on another hit from the Lindquist–Schreiber screen, we recently reported an analogue called synazo-1 that could enhance the antifungal effect of fluconazole with an EC 50 of 300 pM . Encouraged by the discovery of potent fluconazole synergizers we set out to identify new lead compounds, optimize their structures, study their synergy with other azoles, and assess their selectivity for C. albicans .…”