ABSTRACT
Malaria remains one of the most lethal infectious diseases worldwide, and the most severe form is caused by Plasmodium falciparum. In recent decades, the major challenge to treatment of this disease has been the ability of the protozoan parasite to develop resistance to the drugs that are currently in use. Among P. falciparum enzymes, P. falciparum dihydroorotate dehydrogenase has been identified as an important target in drug discovery. Interference with the activity of this enzyme inhibits de novo pyrimidine biosynthesis and consequently prevents malarial infection. Organic synthesis, x-ray crystallography, high-throughput screening and molecular modeling methods such as molecular docking, quantitative structure-activity relationships, structure-based pharmacophore mapping and molecular dynamics simulations have been applied to the discovery of new inhibitors of P. falciparum dihydroorotate dehydrogenase.
Subject(s)
Antimalarials/pharmacology , Enzyme Inhibitors/pharmacology , Malaria/drug therapy , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Plasmodium falciparum/drug effects , Antimalarials/chemical synthesis , Antimalarials/chemistry , Crystallography, X-Ray , Dihydroorotate Dehydrogenase , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Malaria/metabolism , Models, Molecular , Molecular Structure , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Parasitic Sensitivity Tests , Plasmodium falciparum/enzymology , Structure-Activity RelationshipABSTRACT
BACKGROUND: Herpes simplex virus type-1 (HSV-1) is the primary cause of facial lesions (mouth, lips, and eyes) in humans. The widespread use of acyclovir and nucleoside analogues has led to emergence of HSV strains that are resistant to these drugs. Recently, non-nucleoside anti-HSV compounds have received considerable attention. 1,6-Naphthyridines are a class of heterocyclic compounds that exhibit a broad spectrum of biological activities such as inhibitor of HIV-1 integrase, HCMV, FGF receptor-1 tyrosine kinase, and the enzyme acetylcholinesterase. We previously reported the synthesis, SAR studies, and evaluation anti-HSV-1 activity of 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines. In the course of our search for new 1,6-naphthyridines derivatives with potential activity against HSV-1, we have synthesized and evaluated new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines (1a-k) and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines (2a-c). RESULTS: A known synthetic approach was used for preparing new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines (1a-k) and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines (2a-c), starting from ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (7). All compounds were identified by FTIR, 1H NMR, and mass spectrometry. The antiviral effect on HSV-1 virus replication was determined. CONCLUSIONS: The compounds 1d, 1f, 1g, and 1h exhibited the highest anti-HSV-1 activity. In general, 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines were more effective inhibitors than their corresponding 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines. The compound 1h reduced the virus yield in 91% at 50 µM and exhibited a low cytotoxicity (CC50 600 µM).
