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

Among the chemotherapeutic agents against HIV-1 infections, non-nucleosidereverse transcriptase inhibitors (NNRTIs) have gained a definitive and important placefor their unique antiviral potency, high specificity and low toxicity. Along with thedevelopments of molecular modeling, computer aided drug design (CADD) and X-raycrystal technique, NNRTIs were boomed rapidly, to date more than 30 differentclasses of NNRTIs have been reported, among the most representative classes of them,HEPTs and DABOs occupy a relevant position. Recently, based on of Hopkin's postulation and 3D-QSAR studiesof HEPT analogues,our group had successfully designed and synthesized a series of 6-naphthylmethylsubstituted HEPT analogues (HENTs) as high potent HIV-1 inhibitors. In this paper,we further studied the binding model of HENTs against HIV-1 RT by using automatedmolecular docking method. Following the docking results, a 3D-QSAR model wasconstructed by using the approache of CoMSIA. The results indicated that, the N1-substitutent of the uracil situated in a large and flexible hydrophobic pocket of the RT,which contained rich conformations of steric, electrostatic, hydrogen bonding, andhydrophobicity. Thus, new important modifications may be try in this site. First,according to the interaction model of the enzyme-inhibitor complex, this β-oxygen ofN1-side chain interacts with Tyr318 residue of the RT nonnucleoside hydrophobicpocket, the substitution of the oxygen with a carbonyl group, may be benefit to thehydrogen bond between the RT and the inhibitors, Moreover, it will also increase thestability of the 1,6-cis conformation (Kirrev's conclusion from the QSAR studies ofHEPTs) and, hence, increases the probability of improving the activity. Second, on theguild of CoMSIA, different substituted phenyl were introduced to the terminalposition of the N1-side chain to occupy the pocket enough then enhance thehydrophobic interaction between the enzyme and the inhibitor. Last, because manyinhibitor bearing a hydrophobic chain on the N1- position(e. g. MKC-442) wereendowed with a high potent anti-HIV activity, we also introduce some alkoxyl groupsto the N1- position. Based on the above analysis, a series of 5-alkyl-6-naphthylmethyl-1-(aryl or alkyoxyl-carbonyl-methyl) uracils were designed. From the chemical point of the view, DABOs are belonging to the 4-pyrimidinone复旦大学理学博士论文 摘 要series as well as HEPTs. Since the structurally similarity of them, DABOs and HEPTsshare similar chemical requirements for anti-HIV activity, thus, the structure-activityrelationship (SAR) conclusions of HEPTs could further guide the new designs ofS-DABO candidates. The crystallographic analyses and molecular modeling studiesshow that the C2-alkylthio chain of DABOs was locked in the same region of thebinding site as the N1-substituted group on HEPT, so we do the same modification onthe C2- alkylthio chain of DABOs. Following the investigation of the interactionbetween inhibitor and RT enzyme by using molecular docking approach, a series of5-alkyl-6-(1-naphthylmethyl)-2-(aryl or alkyoxyl- carbonyl-methyl) uracil moleculeswere built to evaluate the extent of structural and biological similarities with HEPTderivatives. The synthesis of the two series of novel HEPT and DABO derivatives was carriedout according to the Pederson route. The chloromethyl naphthalene was reacted withsodium cyanide to get the naphthyl acetonitrile, which was reacted with activated zincdust and ethyl 2-bromoalkanoates in THF to afforded the ethyl 2-alkyl-3-oxo-4-napthyl butyrates ( β-Oxo esters). Treatment of β-Oxo ester with thiourea in thepresence of NaOEt in refluxing ethanol to finish the corresponding 2-thiouracil, whichwere refluxed with aqueous chloroacetic acid over night to afford the correspondinguracils. Reaction of thiouracil or uracils with R2COCH2Br in dry DMF in the presenceof K2CO3 to yield the req...