Design, Synthesis And Biological Evaluation Of Novel Oxadiazoles And Imidazopyrazines As Potent HIV-1NNRTIs

Acquried immunodeficiency syndrome(AIDS) is a disease of the human immune system caused by infection with human immunodeficiency virus (HIV). Reverse transcriptase (RT) plays a crucial role in the replication of HIV life cycle, and is responsible for the conversion of the single-stranded RNA viral genome into double-stranded DNA that subsequently integrates into the host DNA.Viral reverse transcriptase is a key enzyme in the replication cycle, therefore it becomes an important target for the design of antiviral drugs.RT inhibitors can be divided into two different classes:nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs).NNRTIs are small molecular allosteric RT inhibitors with chemical diversity, which noncompetitively inhibit DNA polymerization by binding with a non-active site and hydrophobic pocket (termed NNRTIs binding pocket, NNIBP). NNRTIs have been widely used for their high selectivity, relatively low toxicity, and potent activity, which are also an important component of HAART. Another advantage is that they don’t require intracellular metabolism for their activity. Nonetheless, clinical cases with hypersensitivity reactions, Stevens-Johnson syndrome or other adverse effects were appeared. In addition, more drug resistance occurred in patients with failed therapy using rilpivirine as compared to EFV. Consequently, there is a continuous need for next-generation NNRTIs with different resistance profiles and improved safety and tolerability.1. Design, synthesis and biological evaluation of novel oxadiazoles as potent HIV-1NNRTIsBased on the structural features, binding mode and SAR study of2-anilinyl-5-benzyloxadiazole and sulfanyltriazole/tetrazoles NNRTIs, the first oxadiazoles was designed and synthesized. According to the bioisosterism of drug design and molecular hybrid principle, we replaced the aniline group by1,2,3-triazole and all kinds of benzyl group with an attempt to improve the hydrogen bond between the ligand and amino acids of RT. For the preparation of the newly designed series, we choose2-(2,6-dichlorophenyl)acetic acid as the starting material. After reacted with hydrazine hydrate, the first import intermediate2-(2,6-dichlorophenyl)acetohydrazide was obtained, followed by cyclization with carbon disulfide. Then the3-Bromo-l-propyne was attached to the oxadiazole ring. Finally,1,2,3-triazole was synthesized by click chemistry. Twenty compounds were nemly synthesized and confirmed by MS,1H-NMR and13C-NMR. Their activity against wild&mutated HIV-1and cytotoxicity in MT-4cells cannot be detection, probably caused by the instability of the target compounds and complicated mechanism of cell metabolism during activity assay.2. Design, synthesis and biological evaluation of novel oxadiazoles as potent HIV-1NNRTIsOn the basis of the structural biology information of HIV-1reverse transcriptase, we choosed the DAPY NNRTI etravirine as the lead compound and desigened the target compounds by using the bioisosterism strategies. We replaced the pyrimide ring of etravirine with imidazopyrazine ring and retain the phenoxy and aniline part that relates with hydrophobic interaction, generating novel imidazopyrazine series. The imidazole was introduced to the central ring with the aim of interacting with V179. We start our synthesizing work with3,5-dibromopyrazin-2-amine and obtain our target compounds through several steps including cyclization reaction and two substitution reactions. All the compounds were newly synthesized and confirmed by MS,1H-NMR and13C-NMR. Anti-RT assay in vitro indicated that the target compounds showed a wide range of ctivities against HIV-1RT which is superior to NVP. The most potent compound ia MP-4c, possessing inhibitory activity against RT at0.174μM that is comparable to TMC125. The preliminary SAR analysis among the newly synthesized compounds are discussed briefly and tationalized by docking studies, providing a new way of thinking for structure modification.In summary, under the instruction of the principle of bioisosteric replacement and molecular hybrid, we designed and synthesized two series of novel NNRTIs: oxadiazoles and imidazopyrazines. Anti-HIV activity in MT-4cells cannot be detected in oxadiazoles series. Anti-RT assay in vitro indicated that the target compounds showed a wide range of ctivities against HIV-1RT which is superior to NVP and MP-4c possesses inhibitory activity against RT at0.174μM that is comparable to TMC125. Further SAR analysis and structure optimization are in progress.