Novel Aryl Alkamidazole Derivatives as Multifunctional Antifungal Inhibitors: Design, Synthesis, and Biological Evaluation

Abstract

Dual-target drug design was considered as the more reasonable antifungal strategy. In this study, three different series of novel compounds were designed using the skeleton screening and splicing method based on dual-target enzyme features, and their structures were synthesized and characterized. Among them, target compounds 5a-1-2, 14b-1-2, and 14c-2-1 with excellent antifungal activity (0.125−2.0 μg/mL) were selected for the subsequent mechanistic study. On the one hand, these compounds blocked the ergosterol biosynthesis pathway by inhibiting the core enzyme CYP51, which effectively induced rapid accumulation of reactive oxygen species, damaged the mitochondrial function, and eventually led to the occurrence of fungal apoptosis. On the other hand, these compounds also inhibited the inflammatory inducible enzyme cyclooxygenase-2, which further affected the expression of inflammatory factors and body's immune function. In conclusion, this study discovered potential target compounds, which could accelerate the rehabilitation process of the infected region.

Design, Synthesis, and Activity Evaluation of Novel Dual-Target Inhibitors with Antifungal and Immunoregulatory Properties

“…Fungal infection was closely related with inflammatory response; this was due to fungal metabolites or exotoxins that could directly destroy the normal tissue of infection region and activate the expression levels inflammatory factors, which would have the significant impact on the host’s metabolic function and immune system. , COX-2, IL-2, NLRP3, NF-κBp65, and INF-γ were selected as the representative inflammatory factors in the study, and their expression indicators could accurately reflect the development progress of inflammatory reaction in different treatment groups.…”

“…39,40 COX-2, IL-2, NLRP3, NF-κBp65, and INF-γ were selected as the representative inflammatory factors in the study, and their expression indicators could accurately reflect the development progress of inflammatory reaction in different treatment groups.…”

Construction and Evaluation of Novel Dual-function Antifungal Inhibitors and Covalent Organic Framework Carriers Based on the Infection Microenvironment

“…Compared with the pH value (7.35−7.45) of normal tissues and organs, the infection microenvironment of pathogenic fungus shows obvious acidic characteristics, and their pH range was located in the range of 4.0−5.5. 36,37,38 The novel dualtarget compound 14a-2 exerted excellent antifungal activity. In order to further improve the targeting ability, reduce toxic side effects, and prolong action time, the degradable COF was used as the proper delivery carrier of preferred compound 14a-2, which was shown in Figure 11.…”

Construction and Activity Evaluation of Novel Bifunctional Inhibitors and a COF Carrier Based on a Fungal Infection Microenvironment

“…23 Moreover, the corresponding carrier with targeting capability should also be generated to improve the therapeutic effect of novel compounds and eliminate the potential adverse reactions. 24 In the study, the novel dual-target (CYP51/PD-L1) compounds with different skeletal structures were designed, synthesized, and characterized. Their biological activity and action mechanism were evaluated to determine the preferred compounds.…”

“…First, the chloro groups of 2-chloroacetylbenzene 11a, b were substituted with imidazole (triazole) to generate intermediates 12a, b-1, and 2. 31 Their skeleton structures were further transformed into intermediates 13a, b-1, and 2 through epoxidation reaction, and their epoxy groups were opened in alkaline conditions to obtain key intermediates 14a, b-1, and 2. 32 In addition, intermediate 8 further reacted with hydroxybenzaldehyde to produce key intermediates 15 and 16.…”