RESUMEN
Aim: The high incidence and prevalence of fungal infections call for new antifungal drugs. This work was to develop naphthalimide thiazoles as potential antifungal agents. Results & methodology: These compounds showed significant antifungal potency toward some tested fungi. Especially, naphthalimide thiazole 4h with excellent anti-Candida tropicalis efficacy possessed good hemolysis level, low toxicity and no obvious resistance. Deciphering the mechanism showed that 4h interacted with DNA and disrupted the antioxidant defense system of C. tropicalis. Compound 4h also triggered membrane depolarization, leakage of cytoplasmic contents and LDH inhibition. Simultaneously, 4h rendered metabolic inactivation and eradicated the formed biofilms of C. tropicalis. Conclusion: The multifaceted synergistic effect initiated by naphthalimide thiazoles is a reasonable treatment window for prospective development.
Asunto(s)
Antifúngicos/farmacología , Candida tropicalis/efectos de los fármacos , Naftalimidas/farmacología , Tiazoles/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Naftalimidas/síntesis química , Naftalimidas/química , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
Discrimination of phosphomonoesters and phosphodiesters of DNA was attempted with naphthalene diimide carrying two zinc-dipicolylamine (Dpa) units (1). The binding constant of 1 for a self-complementary octanucleotide was 1.3×10(6)M(-1), while the value for the phosphorylated counterpart was 4.8×10(6)M(-1). This fourfold increase in the binding constant seems to stem from higher affinity of the terminal monophosphate over the phosphodiesters of DNA as the fourth ligand for the metal in 1. Likewise, the binding constant of 1 for DNase I-treated calf thymus DNA (average size 200bp) was twice as large as that for untreated DNA (1kb), possibly because the terminal phosphate groups are five times abundant in the former. These findings provide a clue to developing a system where phosphomonoesters generated upon DNA nicking are discriminated specifically from intact phosphodiesters.
Asunto(s)
Aminas/química , ADN/química , Imidas/química , Naftalenos/química , Naftalimidas/síntesis química , Oligonucleótidos/metabolismo , Ácidos Picolínicos/química , Piridinas/síntesis química , Zinc/química , Animales , Bovinos , ADN/metabolismo , Imidas/metabolismo , Ligandos , Naftalenos/metabolismo , Naftalimidas/análisis , Naftalimidas/farmacología , Fosforilación , Piridinas/análisis , Piridinas/farmacologíaRESUMEN
Sleeping sickness caused by Trypanosoma brucei gambiense and rhodesiense is fatal if left untreated. Due to the toxicity of drugs currently used and the emerging resistance against these drugs new lead compounds are urgently needed. Within the frame of a broad screening program for drugs with antitrypanosomal activity, some highly potent tertiary and quaternary mono- and bisnaphthalimides being active in the lower micromolar and nanomolar range of concentration have been identified. These compounds are easily available via a two- or three-step microwave-driven synthesis with high yield.