Synthesis Process Optimization Of Rilpivirine And Design,Synthesis And Biological Evaluation Of Its "Me-Too" Drugs

Acquired immune deficiency syndrome(AIDS),major caused by Human Immunodeficiency Virus type 1(HIV-1)has led to 25 million deaths since its discovery in 1981.Presently,Highly Active Anti-retroviral Therapy(HAART)which combined of different inhibitors,typically including RT inhibitors,is used as the most efficient and standard treatment regimen for HIV-1 infection.Among them,rilpivirine is one of the most important agents in the treatment regimen for AIDS patients.In 2011,rilpivirine,a nonnucleoside RT inhibitor(NNRTI)discovered by the Janssen Pharmaceutica,was approved in the USA as the second-generation NNRTIs after the approved drug Etravirine.Rilpivirine not only have the common advantages of NNRTI drugs of high potency and low toxicity,but also overcome the deficiency of rapid viral drug resistance to the first-generation NNRTI drugs.There is also a higher genetic barrier for HIV-1 to evolve resistance to the two new second-generation NNRTIs.More importantly,rilpivirine is 3-fold more potent than etravirine and is used in a low oral dose(25 mg/tablet)once daily which decrease the drug administration and bring the better choice to the patients.Based on the original patent of rilpivirine,we disclosed an optimized synthesis route of rilpivirine,which have great significance to industrial production.In the first section of this thesis,we mainly focus on the the optimization the synthesis route of rilpivirine to improve the yield and shorten the reaction time.On the basis of the reported synthetic routes,rilpilvirine was prepared by the original compound 2-(methylthio)-4(3H)-pyrimidinone.Then through nucleophilic substitution,chlorination using phosphorus oxychloride as the chlorinating agent and the nucleophilic substitution assisted by the microwave reaction,the final compound was finally obtained.By this means,the total yields of the route increased from 18.5%to 21.5%and the reaction time of the last step decreased from 69h to 90 min.The development of novel NNRTIs with activity against variants of HIV-1 RT is crucial for overcoming treatment failure.Etravirine and Rilpivirine,two diarylpyrimidine(DAPY)derivatives,as second-generation NNRTIs for AIDS therapy,exhibit high potency against wild-type(WT)and a number of mutated viral strains with nanomolar EC50 values.Meanwhile,they also have a higher genetic barrier to delay the emergence of drug-resistance.The successful of the Etravirine and Rilpivirine encouraged further research to explore additional novel DAPYs.And the further modification of the DAPYs resulted in the discovery of many potent compounds with low nanomolar anti-HIV potency against WT and HIV-1 RT-resistant viral strains.The substituents on the 5,6-position of the central pyrimidine ring of the DAPY derivatives was also tolerable.In the present study,a series of novel 6-substituted diarylpyridine derivatives targeting the entrance channel of the NNIBP of RT were designed through a structure-based molecular hybridization strategy.Encouragingly,these new diarylpyridine derivatives were found to be active against wild-type(WT)HIV-1 with an EC50 values ranging from 0.035μM to 1.99μM.Nearly half of them exhibited more potent inhibitory activities in cellular assays than the control drug nevirapine(NVP).Notably,three most promising compounds If(EC50= 35 nM),la(EC50= 43 nM)and Ⅱa(EC50 =41 nM)showed high potency against WT and were comparable to the control drug delavirdine(DLV)(EC50 = 33 nM).Moreover,compounds Ⅰb,Ⅱb and Ⅱh displayed effective activity against the most common clinically observed single and double-mutanted HIV-1 strains in micromolar concentrations.In particular,the inhibition of Ⅱb against the K103N mutation(EC50 = 49 nM),which confers resistance to a wide variety of NNRTIs,was about 140 times than that of NVP(EC50 = 6.78 μM),50 times than that of DLV(EC50=2.48 μM)and about 3 times than that of EFV(EC50 = 0.12 μM),indicating that the newly designed compounds have great potential to be further developed as new anti-HIV-1 agents.Preliminary structure-activity relationships(SARs)and molecular modeling of the new diarylpyridine derivatives were discussed in detail.