Synthesis and anti-HSV-1 evaluation of new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines

Abstract

BackgroundHerpes 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).ResultsA 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.ConclusionsThe 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).

The Role of Pyrazolopyridine Derivatives on Different Steps of Herpes Simplex Virus Type-1 In Vitro Replicative Cycle

“…We have already described the synthesis and antiviral activity of some 1 H -pyrazolo[3,4- b ]pyridine derivatives [ 38 ]. Here, we named the studied compounds ARA-04 , ARA-05 , and AM-57 ( Figure 1 ).…”

“…Moreover, some chemical modifications confer to the biological activity of these derivatives against Alzheimer’s disease and the HIV-1 enzyme reverse transcriptase (RT) [ 33 , 34 ]. In fact, the antiviral activity of the 1 H -pyrazolo[3,4- b ]pyridine and thieno[2,3- b ]pyridine derivative systems was described by our group [ 35 , 36 , 37 , 38 , 39 ].…”

“…Our group demonstrated the inhibition of HSV-1 cytopathic effects by 1 H -pyrazolo[3,4- b ]pyridine derivatives [ 38 ]. However, the mechanism of action towards this virus replication remained to be characterized.…”

Perillyl Alcohol and Perillic Acid Exert Efficient Action upon HSV-1 Maturation and Release of Infective Virus

“… Vero cells were infected with KOS and 17 syn + virus strains and determined the cytotoxicity (CC 50 ), antiviral activity (EC 50 : KOS) and selectivity index (SI = CC 50 /EC 50 ) of monoterpenes perillyl alcohol (POH), perillic acid (PA) and acyclovir (ACV). Results represent mean ± sd of three experiments. aReference data [50]. …”

Update On Emerging Antivirals For The Management Of Herpes Simplex Virus Infections: A Patenting Perspective

“…A series of compounds were tested against HSV-1 and 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines were found to be more effective inhibitors than their corresponding 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines. Among all the active compounds, 6-chloro-3-phenyl-9-fluoro-3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine reduced the virus yield by 91% at 50 μM and exhibited a low cyto-toxicity (CC 50 =600 μM) [124]. …”