Design, Synthesis And SAR Research Of Diaryltriazine Analogues, 6-naphthoxy Substituted And 6-(α-Cyano-benzyl) Substituted S-DABO Analogues As Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

AIDS(acquired immune deficiency syndrome) caused by the human immunodeficiency virus(HIV) is an incurable disease.The virally encoded HIV-1 reverse transcriptase(RT) is considered as one of the most attractive targets for the development of new antiviral drugs.The structure-activity relationship(SAR) studies of diaryltriazine(DATAs) and di-hydro-alkoxybenzyloxopyrimidinone(DABOs) as two kinds of non-nucleoside reverse transcriptase inhibitor(NNRTI) are presented in the first chapter of this thesis. The SAR profile of DATA reveal that the 4-cyano anilino moiety(Ar₂) at C-2 of the triazine ring is crucial for the antiviral activity,the cyano group forms dipole interaction with amino residue Gly138 of reverse transcriptase(RT).The aromatic ring at C-6(Ar₁) of the skeleton is situated in a large and flexible hydrophobic pocket of HIV-1 RT,whose volume of substituent is critical for potency,while the C-4 moiety of the triazine is located at the opening of the binding pocket,which could be able to accommodate a large of structural changes.The SAR studies on S-DABOs reveal that a major determinant of increased potency in these new congeners is the improved interactions between the residues Tyr188,Tyr181 in the hydrophobic binding pocket of RT and the C-6 aromatic ring of the inhibitors.The C-2 substituent of S-DABOs situated in a large and flexible hydrophobic region of the binding site of RT,which could accommodate a number of different kinds of subsitutent varied from alkyl to arylmethyl groups.3D-QSAR studies were established on 35 known DATAs by CoMFA in chapter 2, the result indicated that more bulk at the C-6 position of the triazine was preferable, while high electronic density was tolerated at C-4 moiety,whereas electronic deficiency at Ar₂ was favored.At the first part of chapter 3,the SAR conclusion of DATA and the computation on volume and surface of lead compounds R106168 and R120393 indicated that the following modifications would be favorable for their anti-HIV-1 activities: replacement of the phenyl moiety with a naphthyl group of C-6 position as Ar₁ to strengthen theЛ-Лstacking interaction with RT residues Tyr188,Tyr181 and Trp229; modification of the 4-position of the triazine with amine and azido group to increase electronic density;incorporation of fluorine into position 2 of Ar₂ to affect biological properties associated with lipophilicity,absorption and transportation.Guided by our previous work on S-DABOs,we mainly focused our attention on the structural variation on C-6 of pyrimidine ring at the second part of this chapter:1) a cyano group was introduced to the aryl methylic carbon at C-6 position of the pyrimidine ring;2) replacement of the methylic carbon by oxygen as bioisosterim to explore further SAR.Thus,90 new target compounds including 69 DATAs and 21 S-DABO were designed and synthesized,whose structure were confirmed by spectroscopic data as IR,MS,NMR and elemental analysis.In chapter 4,all new target compounds in DATA and S-DABO series were evaluated for their cytotoxicity and anti-HIV activity in MT-4 cells in comparison with DDI and nevirapine.It was found that 42 DATA compounds(xyz-11～xyz-97, xyz-F01～xyz-F22,xyz-F61～xyz-F87,IC₅₀:0.0080±0.004～4.91±0.78μM) showed more potent anti-HIV-1 activities than the reference compounds DDI.Among which, 16 compounds were proved to be approximately 1 to 59-fold more active than nevirapine.It is worth mention that 5 DATA analogues(xyz-31,xyz-61,62 and xyz-80,81) were proved to be highly effective in inhibiting HIV-1â…¢B replication at nanomolar concentrations(0.004-0.009μM) and high selectivity(SI= 5000-40000); xyz-31,xyz-61,62 and xyz-80,81 exhibited activity against Y181C and K103C HIV-1 double mutant strain at micromolar concentration..In the series of S-DABO, only 3 compounds(L1,J3,J4) were endowed with potency.Based on the CoMFA and CoMSIA model,the further SAR of novel DATAs were explored and analyzed in the aspects of stedc,electronic and hydrophobic fields in chapter 5.The 2D-QSAR between activity and quantum parameters or other descriptors of new DATAs were studies by the methods of Hansch.The conclusions summarized from these results will provide useful information for design new DATA analogs as potent HIV-linhibitors.