Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans

Abstract

We investigated the antifungal activity of fused Mannich ketone (FMK) congeners and two of their aminoalcohol derivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC90s) ranging from 0.8 to 6 µg/mL toward C. albicans and the closely related C. parapsilosis and C. krusei while having reduced efficacy toward C. glabrata and almost no efficacy against Aspergillus sp. Transcript profiling of C. albicans cells exposed for 30 or 60 min to 2-(morpholinomethyl)-1-indanone, a representative FMK with a five-membered saturated ring, revealed a transcriptional response typical of oxidative stress and similar to that of a C. albicans Cap1 transcriptional activator. Consistently, C. albicans lacking the CAP1 gene was hypersensitive to this FMK, while C. albicans strains overexpressing CAP1 had decreased sensitivity to 2-(morpholinomethyl)-1-indanone. Quantitative structure–activity relationship studies revealed a correlation of antifungal potency and the energy of the lowest unoccupied molecular orbital of FMKs and unsaturated Mannich ketones thereby implicating redox cycling-mediated oxidative stress as a mechanism of action. This conclusion was further supported by the loss of antifungal activity upon conversion of representative FMKs to aminoalcohols that were unable to participate in redox cycles.

Mannich bases in medicinal chemistry and drug design

“…35), except that the MIC values for compounds 195 were consistently better than those for Mannich bases 194 [300]. Transcript profiling of C. albicans cells treated with candidate 195 (n ¼ 0, NR 2 ¼ 4-morpholinyl) showed that the transcriptional response is typical for oxidative stress and similar to that of a C. albicans Cap1 transcriptional activator, which suggests that the ability of Mannich bases 195 to directly trigger oxidative stress may be at least in part the reason for their antifungal activity [300]. Mannich bases 196 of thiocroman-4-ones ( Fig.…”

Mannich Ketones as Possible Antimycobacterial Agents

“…Previously, the antibacterial effect of these molecules has been found to depend on their hydrophobic character , that is, a lipophilic molecule may better penetrate through the typically hydrophobic mycobacterial cell wall. Based on literature data and calculating the logarithm of n ‐octanol/water partition coefficients (log P; Table S1 in the Supporting Information) as a measure of lipophilicity for the compounds included in our present investigation ( 1 – 23 ), some more hydrophobic unsaturated Mannich ketones with seven‐ and eight‐membered rings also have been selected for evaluation in this study.…”

“…Some known Mannich ketones were screened against several mycobacteria, including explorations of their mechanism of action. Several Mannich ketones have been reported as potent antifungal , cytotoxic and antimycobacterial agents . Mannich ketones are able to undergo 1,2‐elimination–deamination affording reactive vinyl ketone intermediates that show addition reactions with thiols .…”

“…Previously, we synthesised two families of Mannich ketones as water‐soluble hydrochlorides: cyclic α,β‐unsaturated Mannich ketones and the fused cyclic Mannich ketones . They have been screened against pathogenic standard bacterial strains and pathogenic yeasts . From these structures, we have selected for antimycobacterial screening a molecular library containing rings of different sizes and with variable amine side chains, as well as different benzocycloalkanones and varied substitution patterns to study structure–activity relationships and to select promising lead compounds for further therapeutic exploration (Figs.…”

“…). A representative compound of the library (2) has been determined non‐toxic in mice with LD 50 value as high as 450 mg/kg body weight after intraperitoneal administration .…”