Structure-based Design,Synthesis And Biological Evaluation Of Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

Acquired immunodeficiency syndrome (AIDS) mainly caused by human immunodeficiency virus type-1 (HIV-1) continues to be one of the most serious diseases throughout the world. Although the clinical usage of highly active antiretroviral therapy (HAART) has extensively reduced the morbidity and mortality in the AIDS patients, the rapid emergence of drug resistance and several serious side effects during the long-term therapy are tremendous challenges for eradicating HIV-1 infection. Therefore, the AIDS prevention and treatment are still major health and medicinal problems worldwide.HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are indispensable components of HAART regimen for their high specificity, robust inhibitory potency and low cytotoxicity. However, they are also compromised by the drug-resistance. Therefore, there is an urgent need to further discover novel HIV-1 NNRTIs with higher oral bioavailability, better pharmacokinetic properties, lower cytotoxicity and improved anti-resistance profiles.The research work in this thesis could be divided into two sections, which were summarized as follows:Section One:Design, Synthesis and Biological Evaluation of S-DABOs Derivatives.Continuing our research to obtain more effective S-DABOs by further exploring the relationship between the C-6 substituent of pyrimidinone core and their antiviral activities, we introduced an adamantylmethyl group which was identified as a privileged antiviral motif into C-6 position, and designed and synthesized a series of dihydro-arylthio-adamantylmethyl-oxopyrimidines with various substituents (including the previously disclosed preponderant groups) at C-2 side chain and a methyl or ethyl group at C-5 of the pyrimidinone ring. These newly synthesized compounds were evaluated for their anti-HIV activities and HIV-1 RT inhibitory activity. In addition, the structure-activity relationship (SAR) analysis and molecular simulation studies of these title compounds have also been discussed in view of further investigations.It was shown that majority of these series of compounds displayed moderate efficiencies in inhibiting the replication of the HIV-1 IIIB with EC50 values in the range from 0.10 μM to 5.39 μM. In particular, compounds IB-1、IB-2 and IB-3 proved to be potent molecules with EC50 values of 0.10 μM,0.19μM and 0.12μM (SI= 102-172), respectively, which were more potent than the reference drug NVP (EC50= 0.26 μM), but still inferior to AZT (EC50= 0.0067 μM), DLV (EC50= 0.033 μM), EFV (EC50= 0.0054 μM) and ETR (EC50= 0.0035μM). In addition, compounds IB-4, IB-9 and IB-10 also exhibited promising anti-HIV-1 activity with EC50 values of 0.27 μM,0.25 μM and 0.30 μM, respectively, which were comparable to those obtained for NVP. Overall, the newly synthesized compounds had activities against WT HIV-1 (ⅢB), which indicated that the C-6-adamantylmethyl substituent could make the hydrophobic interactions and van der Waals contacts of inhibitors with binding pocket of RT. Unfortunately, none of these compounds was active against the HIV-1 mutant strain RES056 (K103N/Y181C) at subtoxic concentrations.The SAR analysis displayed that (ⅰ) introduction of a bulky group into the C-5 position contributes to enhance the hydrophobic interactions with the binding pocket of the HIV-1 RT, and, this reinforces their potency against WT HIV-1; (ⅱ) Introduction of arylcarbonylmethylthio into C-2 position of pyrimidinone ring resulted in compounds with highly potent activity. Extending the C-2 arylcarbonylmethylthio group to phenylaminocarbonylmethylthio led to compounds with slightly decreased activity; (ⅲ) Among the 2-phenylaminocarbonylmethylthio-5-ethyl analogues, the antiviral potency of para substituent at the phenyl ring of C-2 side chain increased in the order of SO2NH2> COMe> CONH2> CN> H> Me.Compound IB-1 was selected to evaluate HIV-1 RT inhibitory activity. It was shown that compound IB-1 exhibited potent RT inhibitory activity with an IC50 values of 3.37 μM, which was more potent than NVP (IC50= 8.78 μM) and comparable to TMC125 (IC50= 3.10μM). The results confirmed that the representative compound displayed high affinity to HIV-1 RT and the newly synthesized inhibitors could act as NNRTIs.Section Two:Design, Synthesis and Biological Evaluation of IASs Derivatives.Based on the SAR analysis of previously reported indolyl aryl sulfone (IAS) derivatives, we maintained the core of indolyl sulfone and introduced an acrylamide or vinyl sulfonyl chloride group into alkyl rings near the 181C residue in Y181C RT NNIBP. It was explored whether it could specifically make an interaction with the SH group of 181C residue through a Michael addition reaction, aiming to enhancing the activity against the Y181C mutant HIV-1 strain. The alkyl rings vary (four-, five-and six-member rings) to keep the structural diversities and 10 compounds were finally synthesized. Then four compounds were selected to evaluate HIV-1 RT inhibitory activity. Results showed that compound IIA-2 possessed certain inhibition rate against WT RT. The anti-HIV activity and HIV-1 Y181C RT inhibitory activity are being evaluated.In summary, based on the SAR and molecular modeling studies, maintaining previously disclosed preponderant groups, we designed and synthesized 30 new compounds belonging to two series of NNRTIs, which were worth further investigation and development. Biological activities showed that new S-DABO derivatives possessed moderate activity, which provided evidences for further research and development.