Chemistry and anti-herpes simplex virus type 1 evaluation of 4-substituted-1H-1,2,3-triazole-nitroxyl-linked hybrids.

HSV disease is distributed worldwide. Anti-herpesvirus drugs are a problem in clinical settings, particularly in immunocompromised individuals undergoing herpes simplex virus type 1 infection. In this work, 4-substituted-1,2,3-1H-1,2,3-triazole linked nitroxyl radical derived from TEMPOL were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. The nitroxide derivatives were characterized by infrared spectroscopy and elemental analysis, and three of them had their crystal structures determined by single-crystal X-ray diffraction. Four hybrid molecules showed important anti-HSV-1 activity with IC50 values ranged from 0.80 to 1.32 µM. In particular, one of the nitroxide derivatives was more active than Acyclovir (IC50 = 0.99 µM). All compounds tested were more selective inhibitors than the reference antiviral drug. Among them, two compounds were 4.5 (IC50 0.80 µM; selectivity index CC50/IC50 3886) and 7.7 times (IC50 1.10 µM; selectivity index CC50/IC50 6698) more selective than acyclovir (IC50 0.99 µM; selectivity index CC50/IC50: 869). These nitroxide derivatives may be elected as leading compounds due to their antiherpetic activities and good selectivity.

Virtual screening identified compounds that bind to cyclin dependent kinase 2 and prevent herpes simplex virus type 1 replication and reactivation in neurons.

HSV-1 is one of the most prevalent viruses worldwide, and due to the limited therapies mainly with acyclovir and analogues and the emergence of acyclovir (ACV) resistant strains, the search for new drugs with different modes of action is needed. This study identified compounds that bind in silico to cyclin dependent kinase 2 (CDK2), a cellular enzyme required for efficient HSV-1 replication, and have anti-HSV-1 activity. Compounds obtained from virtual screening by Pharmit were filtered in FAF-Drugs4 for good pharmacokinetic and toxicological profiles and submitted to molecular docking on CDK2 using Autodock Vina. The six most promising compounds were evaluated for inhibiting lytic replication of HSV-1 wild-type and ACV-resistant strains on human fibroblasts. The compounds were also assayed for cytotoxicity. Compounds 1, 2 and 3 showed antiviral activity with EC50 (50% of effective drug concentration) of 32, 29 and 64 µM and CC50 (50% of cytotoxic concentration) of 159, 1410 and 2044 µM, respectively. Compounds 1 and 2 were also active against ACV resistant strains and compound 3 inhibited the reactivation of HSV-1 in neurons, which is an important finding to guide drug design of new anti-HSV-1 antivirals with different modes of action. These compounds are promising candidates for optimization into more potent agents to treat HSV-1 infections and recurrences.