Design, Synthesis And Antiviral Evaluation Of Etravirine Analogues As Potent HIV-1NNRTIs

According to the latest data released by Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO), there are2.6million people newly infected with human immunodeficiency virus type1(HIV-1) in2009as compared to2.5million people newly infected in2007. The most efficient and standard treatment regimen for HIV-1infection is highly active antiretroviral therapy (HAART). As a key component of HAART, NNRTIs present higher specificity and lower toxicity.NNRTIs targeted at a hydrophobic binding site (namely NNIBP), which is located at a short distance of10A from the catalytic site. The NNIBP has high flexibility as it does not exist until binding with NNRTI In addition, mutations can be observed frequently in and around the NNIBP. Etravirine possesses excellent broad spectrum antiviral potency attributing to their structurally intrinsic flexibility, and readily adapted conformation to adjust to the NNIBP rearrangements caused by drug-resistant mutants. Once etravirine was approved in2008, the research of etravirine became a hotspot, which resultting a group of active etravirine analogues.The thesis use etravirine as a reference drug and design target compounds based on bioisosterism principle and computer aided drug design strategy (molecular modeling). We replace the pyrimidine ring of etravirine with pyridazine or pyridazinone rings and retain the phenoxy and aniline part that relates with hydrophobic interaction, hydrogen bonding, generating novel pyridazine or pyridazinone series as etravirine analogues. We start our synthetizing work with3,6-dichloropyridazine and obtain our target compounds through several steps including ammoniation, bromination, diazotization, chlorination, two substitution reactions and hydrolysis reaction.26compouds are newly synthetized and confirmed by MS and1H-NMR.The anti-HIV-1(â…¢B), HIV-1(RES) and HIV-2(RoD) potencies of our target compounds are tested. The results indicate that most of target compounds have potency against wild-type HIV-1(B), such as compounds F1, F8, G1and G8. The most effective compound is F7with EC500.034ÎœM against wild-type HIV-1, and with selective index value of563. The potency of F7is high than nevirapine and delavirdine but lower than efavirenz and etravirine.In summarize, our group use etravirine as a reference drug and design target compounds based on bioisosterism principle, generating novel pyridazine or pyridazinone series as etravirine analogues.26compouds are newly synthetized and tested their anti-HIV-1potency. According to the activity test we retain several inhibitors with higher potency than nevirapine and delavirdine but lower potency than efavirenz. So the novel pyridazine and pyridazinone compounds need futher modification.