Molecular Design,Synthesis And Biological Activity Research Of 6-Naphthylmethyl Substituted HEPT Analogs As Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors

AIDS (Acquired immune deficiency syndrome) is caused by HIV (Human immunodeficiency virus). It attacks and destroys the body's defense system that fights against infection. A person suffered with this disease has little ability to fight off many other diseases including pneumonia, cancer and tuberculosis. Certain enzymes including reverse transcriptase (RT) produced by HIV play an important role in making new copies of HIV. The virally encoded HIV-1RT provides an important target for the development of anti-AIDS drugs. Present chemotherapeutic agents against HIV-1 RT interfere with the polymerase activity of the RT enzyme and can be divided into two classes: nucleoside and non-nucleoside RT inhibitors (NRTIs and NNRTIs). With their merit combination of high potency, low toxicity and exquisite selectivity, HEPT analogs MKC-442 were initially considered as candidates for AIDS therapy. The previous studies of the structure-activity relationships (SAR) of HEPT analogs indicated that the following modifications would be favorable for their anti-HIV-1 activities: replacement of the 5-methyl group with a bulkier alkyl group such as an ethyl or an isopropyl group; modification at the 3- and 5-position of the C-6 phenylthio ring with methyl groups of halogen atoms; replacement of the 2-oxo function with a thione function; removal of the hydroxyl group in the N-1-(2-hydroxyethoxy)methyl side chain. Our recent 3D-QSAR (CoMFA) study of 35 HEPT analogs revealed that the suitable length of N-1 side chain is crucial for the antiviral activity. Crystal structure of HIV-1 RT complexed with a range of chemical diverse NNRTIs have shown a single pocket in which the inhibitors bind and details of the inhibitors-protein interaction. Complexes of HIV-1 RT with of HEPT inhibitors reveal conformational changes, which correlate with changes in potency and relevant to the design of potent NNRTIs. The roof of the pocket has a particularly hydrophobic surface, and it is observed that significant nearby volume remains unexploited. It may be possible and benefit to accommodate a 6-naphthylmethyl group as a replacement for the 6-benzyl group. With the above SAR knowledge in mind, by analyzing the hydrophobic environment of the NNRTBP, we take the HIV-1 RT as the target enzyme and chose MKC-442 as the leading compound for further structural modification. Two series of target compounds derived from of MKC-442 were designed and synthesized. It was reported that the 6-cyclohexylthio substituent of TNK-6123, which has been designed as HIV-1 RT inhibitor against the drug-resistant HIV-1 mutants, could fill the upper sub pocket of the NNRTI binding site and thus adopt the lowest energy chair conformation. 1-[(2-Hydroxyethoxy)methyl]-6-[1-(5,6,7,8-tetrahydronaphthyl) methyl]thymine as new HEPT analogs containing cyclohexyl group was also designed and synthesized. Different synthetic routes were explored and applied to obtain these structural different target compounds successfully. The chloromethylation of naphthalene give the chloromethyl naphthalene, which was reacted with sodium cyanide to get the naphthyl acetonitrile. Naphthylacetonitrile was reacted with an α-bromo ester to give the enamine ester and then hydrolyzed to the β-oxo ester. The β-keto ester was condensed with thiourea in the presence of sodium ethoxide to furnish the corresponding thiouracil, which can afford the uracil in boiling aqueous chloroacetic acid by exchanging sulfur with oxygen. The pyrimidine was silylated with HMDS or BSA and underwent alkylation with chloromethyl alkyl ether or dioxalane in the presence of Bu4NI or SnCl4 to afford the series compounds of 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils. Trimethylsilyl protected thymine was reacted with dioxalane and SnCl4 to give 1-[(2-hydroxyethoxy)methyl]thymine. Further protection of hydroxyl group on side chain with TBDMSiCl gives 1-[(2-tertbutyldimethylsilyloxyethoxy)methyl]thymine, which was lithiated with LDA and reacted with naphthaldehydes to give 1-[(2-tertbutyldimethylsilyloxyethox...