ABSTRACT
Over the years, the development of bioactive heterocycles has aroused the interest of the scientific community, because in general, these heterocycles are strategic in maintaining life. Research into bioactive heterocycles is associated with the development of methods of synthesis and the biological evaluation of different nuclei. In consequence, there has been a growing interest in the nucleus of fused pyrimidine, which has diversified pharmacological activities, including diuretic, antimicrobial, antifolate, tyrosine kinase, anti-inflammatory, anticancer, anthelminthic, and antiviral activities. This review focuses on describing a diverse set of structures derived from pyrimido[4,5-d]pyrimidines and contemplates the main bioactivities of these nuclei.
Subject(s)
Pyrimidines/pharmacology , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Diuretics/pharmacology , Folic Acid Antagonists/pharmacology , Humans , Protein-Tyrosine KinasesABSTRACT
This work describes the antitrypanocidal activity of two hydroxamic acid derivatives containing o-ethoxy (HAD1) and p-ethoxy (HAD2) as substituent in the aromatic ring linked to the isoxazoline ring. HAD1 and HAD2 induced a significant reduction in the number of intracellular parasites and consequently showed activity on the multiplication of the parasite. Treatment of cardiomyocytes and macrophages with the compounds revealed no significant loss in cell viability. Ultrastructural alterations after treatment of cardiomyocytes or macrophages infected by Trypanosoma cruzi with the IC50 value of HAD1 revealed alterations to amastigotes, showing initial damage seen as swelling of the kinetoplast. This gave a good indication of the ability of the drug to permeate through the host cell membrane as well as its selectivity to the parasite target. Both compounds HAD1 and 2 were able to reduce the cysteine peptidases and decrease the activity of metallopeptidases.
Subject(s)
Chagas Disease/drug therapy , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Cells, Cultured , Chagas Disease/microbiology , Dose-Response Relationship, Drug , Hydroxamic Acids/chemical synthesis , Macrophages/drug effects , Macrophages/microbiology , Mice , Molecular Structure , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/microbiology , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesisABSTRACT
BACKGROUND: 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole (DIC) is a five-membered heterocyclic compound containing a N-O bond. The anti-inflammatory effects of this compound were studied both in vitro and in vivo. PRINCIPAL FINDINGS: DIC effectively decreased TNF-α and IL-6 release from LPS-stimulated macrophages in a dose dependent manner. DIC diminished the levels of COX-2 with subsequent inhibition of PGE(2) production. DIC also compromised HMGB1 translocation from the nucleus to the cytoplasm. Moreover, DIC prevented the nuclear translocation of NF-κB and inhibited the MAPK pathway. In vivo, DIC inhibited migration of neutrophils to the peritoneal cavity of mice. CONCLUSIONS: This study presents the potential utilization of a synthetic compound, as a lead for the development of novel anti-inflammatory drugs.
