Molecular Design And Synthesis Of DBO2 Analogues For Non - Nucleoside HIV Retrograde Enzyme Inhibitors

Acquired immunodeficiency syndrome (AIDS) is a worldwide pandemic disease caused by the human immunodeficiency virus (HIV). Due to its important role in the HIV-1life-cycle, The reverse transcriptase (RT) has been identified as a prime target for anti-HIVdrug discover.According to the molecular structure and different interaction mechanisms with RT, HIV reverse transcriptase inhibitors are divided into two categories:nucleoside reverse transcriptase inhibitors (NRTIs/NtRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Among them, NNRTIs, with its high efficiency low toxicity, the variety of structure types and other characteristics, has been the hot spot of anti-HIV-1drugs’research and development. Although treatment of HIV-1with highly active antiretroviral therapy(HAART) is effective in preventing acquired immune deficiency syndrome, it cannot eradicate the virus and is associated with drug resistance. Therefore, more effective, safer and economical drugs targeting drug-resistant virus are urgently needed.Our continuing interest in the search for new NNRTIs led us recently to describe the design and synthesis of a new series of dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines (S-DACOs) as highly potent HIV-1inhibitors. Among them,6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio) pyrimidin-4(3H)-one (DB-02), exhibited good potential as anti-HIV drug candidate. Structure-activity relationships(SAR) studies revealed that it is very important when cyclohexyl is introducted at C-6, which eliminate the dependency on the interaction between the aromatic ring in Y181or Y188and improve the activity to anti Y181C mutation. The SAR studies also indicated that the cyclohexyl was deeper entered the hydrophobic pockets, but there is still a larger distance from the conservative amino acid residue W229at the top of the pocket, which provided a large room for the improvement of further structure modification. In this paper, we studied the putative binding mode of DB02to the active site of RT to achieve further modifications on this series of NNRTIs. In this study, designed and synthesized series4-(2-(4-(piperidin methyl)-5-alkyl-6-oxo-1,6-dihydro pyrimidine-2-ylsulfanyl) acetyl)-4-substituted benzoic acid phenyl ester compounds by performing computer aid drug design methods.The target compounds were synthesized starding from1-Boc-4-piperidine acetic acid which was first converted to β-ketoesters by improved Clay route. Then condensation of β-ketoesters with thiourea in the presence of NaOEt in refluxing ethanol gave the key intermediate5,6-double substituted pyrimidone.. Finally, the desired target compounds were prepared by the selective S-alkylation of above pyrimidone with the appropriate4-(2-bromoacetyl)phenyl aryl/alkyl ester in the presence of K2CO3in anhydrous DMF. The4-(2-bromoacetyl)phenyl aryl/alkyl ester were obtained by using various substituted acid and p-hydroxybromoacetophenone as the raw materials in the heating system H3PO4/TFAA. The production rate was improved by optimizating the experimental conditions. In this paper, more than50intermediates and final products were synthesized in this paper, and among them,34compounds were the target molecules which have not been reported in literature. The structures of all these target compounds were confirmed by1H NMR,13C NMR, FT-IR and ESI-MS.In this paper, the biological activity test of the target compounds in vitro will be tested by the Rega Institute of Belgium University, but it is still ongoinguntil this paper were accomplished.