Design, Synthesis And Anti - HIV Activity Of 6- (piperidine - 4 - Methyl) - DABO - Like

Acquired immunodeficiency syndrome (AIDS) is a worldwide pandemic disease caused by the human immunodeficiency virus (HIV). The reverse transcriptase (RT) of HIV, being the primary enzyme responsible for the conversion of the viral single-stranded RNA to the double-stranded DNA chain that subsequently is incorporated into the DNA of the infected host cell, remains one of the most attractive targets for the development of new anti-HIV/AIDS drugs. Non-nucleoside reverse transcriptase inhibitors (NNTRIs) with structural diversity have, in addition to other kinds of drugs, gained a significant place in the treatment of HIV-1infections because of their low toxicity, high potency, and statistical synergy with other anti-HIV drugs. However an obvious disadvantage of NNRTIs is rapid emergence of virus-drug resistance due to mutations of the amino acids surrounding the NNRTIs-binding site. Therefore, it is critical to explore novel types of NNRTIs effective against drug-resistance. This research was focused on seeking a novel class of potent NNRTIs leads following the bioisosterism principle and scaffold hopping strategy based on the structure of target binding site.We have been actively involved in chemical synthesis and biological evaluation of a new class of molecules, dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines (S-DACOs) via computer aid drug design and pharmacology and toxicology study. In this paper, the putative binding mode of S-DACOs to the active site of RT was studied by the means of LigandFit, which provide some useful indications for guiding the further rational design of new S-DACO analogues. With the aim to improving its anti-resistant activity and oral bioavailability, we mainly focused our attention on the structural variations on the C-2, C-5and C-6substitutents of S-DACOs. A series of the new compounds6-(piperidin-4-yl)methyl-DACOs were designed and their feasibilities also be analysed by using molecular docking methods.Different synthetic routes were explored and applied successfully to obtain these target compounds. The synthesis of the series of β-keto esters was carried out according to the Clay route. Treatment of β-Oxo ester with thiourea in the presence of NaOEt in refluxing ethanol to finish the corresponding2-thiouracil, thiouracil with RBr in dry DMF in the presence of K2CO3to yield the required TM-Ⅰ derivatives. Then under the condition of trifluoroacetic acid to take off the protection and with acetyl chloride or methanesulfonyl chloride reaction to yield the required TM-Ⅰ、 Ⅲ target molecules. More than50intermediates and final products were synthesized in this paper, and among them30compounds 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.The novel compounds were evaluated for their anti-HIV activity and toxicity in C8166cells. The date indicates that some compounds show obvious anti-HIV-1biological activity and less cytotoxicity. ZMP-06、ZMP-09、ZMP-21、ZMP-22、 ZMP-23、ZMP-24、ZMP-25show obvious anti-HIV-1biological activity and most of compounds have less cytotoxicity(CCso>400μM).