Design,Synthesis And Biological Evaluation Of Novel HIV-1 NNRTIs And RT/NCp7 Dual Inhibitors

Acquired Immunodeficiency Syndrome(AIDS)is a chronic,potentially life-threatening disease caused by the human immunodeficiency virus(HIV).HIV-1 is the most common type of pathogen for AIDS.The reverse transcriptase(RT)enzyme plays a significant role in the HIV life cycle with a precise mechanism of action and protein structure.Among nucleoside and non-nucleoside inhibitors,HIV-1 non-nucleoside reverse transcriptase inhibitors have achieved significant importance in drug discovery due to their high efficiency,low toxicity,and strong specificity,thus attained as a great part of highly active antiretroviral therapy(HAART).However,since the amino acid residues at the binding site of NNRTIs are prone to mutations,this type of drug is prone to drug resistance and rapidly reduces clinical potency.Therefore,there is an urgent need to develop new inhibitors with chemical diversity,more efficient,low-toxic,improved tolerability,and resistance profiles,especially other types of NNRTIs.Indolylarylsulfone(IAS)compounds are a unique class of HIV-1 NNRTIs.To improve the anti-HIV-1 activity and optimize physicochemical properties and pharmacokinetics,substantial research is going on IAS,and the majority of work was carried on the structural modification of 2-carboxamide region.The activity results also proved that this position is a favorable site for structural modification.In this basically unchanged skeleton of the protein,it is essential to increase the interaction forces between the drug and the target to maintain the affinity and overcome the drug resistance caused by the amino acid mutation in the ligand-binding site.In addition,a multi-target drug design can also overcome the emergence of drug resistance to improve the therapeutic effect.Improving the pharmacokinetic properties of drugs is also a significant link in research&development.With the aim of improving the resistance profile of IASs and optimize the pharmacokinetic properties,this thesis represents the structural modification of 2-carboxamide nitrogen of IASs and the results.Design,synthesis and biological evaluation of novel indolylarylsulfones bearing Arenylboronic acid functionalities as potent HIV-1 NNRTIs.IASs/RT co-crystal structures indicate that the indole 2-position toward the flexible channel composed of L100,G138 and V179 is a favorable structural modification site.Based on the ability of boronic acid to form multiple hydrogen bonds,we designed and synthesized a series of novel IAS HIV-1 NNRTIs bearing phenylboronic acid at indole-2-carboxamide,hoping the compounds to form extensive hydrogen bonds with the amino acid residues of the entrance channel to improve drug resistance profile.The antiviral results at the cellular level showed that all boronic acid derivatives showed strong inhibitory activity against wild-type HIV-1(EC50(ⅢB)=6.7-42.6 nM).In particular,the representative compound SC-5d(EC50(ⅢB)=8.5 nM)maintained its inhibitory activity against L100I,K103N and V106A/F227L mutant strains(EC5(L100I)=7.3 nM;EC50(K103N)=9.2 nM;EC50(F2271/V106A)=21.1 nM),far superior to the marketed drugs nevirapine,lamivudine and efavirenz,and at the same level as etravirine.In the enzyme inhibition assay,the compound SC-5d exhibited superior binding-affinity to WT HIV-1 RT in comparison to etravirine.Most importantly,compound SC-5d possessed significantly improved water solubility compared to ETV under different pH conditions.We also introduced the Fsp3 concept,incorporating a spiro structure with three-dimensional structure and structural novelty to the 2-carboxamide nitrogen of the indole nucleus.The larger three-dimensional structure allows the molecule to occupy more chemical space and establish potential interactions with surrounding residues,thereby enhancing the affinity with the target.On the other hand,it is expected to increase the solubility of the compound.This series of compounds are now under antiviral activity evaluation,and results will be published soon.Design,synthesis and biological evaluation of novel HIV-1 RT/NCp7 dual-target inhibitors based on a new mechanism of actionDesigned multiple ligands(DMLs)therapy as an emerging anti-HIV drug discovery paradigm,using a single entity to inhibit multitargets could yield improved patient compliance,thus reducing the likelihood of drug resistance.The exploration of such multifunctional ligands has proven valuable for anti-HIV leads discovery.HIV-1 nucleocapsid protein 7(NCp7)inhibitors can not easily develop drug resistance due to NCp7 gene mutations and are a class of inhibitors with a high resistance barrier.And NCp7 often forms a protein complex with reverse transcriptase when it performs biological functions.S-acyl-2-meraptobenzamide thioester(SAMT)is an attractive class of NCp7 inhibitors due to its high resistance barrier and low toxicity.Therefore,we adopted the designed multiple ligands(DMLs)strategy using indolylarylsulfone NNRTIs and SAMT as the parent drugs through conjugating these two pharmacophores.Based on this strategy,we designed and synthesized a series of RT/NCp7 dual-target inhibitors.It is expected that the designed target compound can have the advantages of the two-parent drugs(high anti-HIV-1 activity and high resistance).Cell-based anti-WT HIV-1 activity results revealed that:some IASs have low toxicity and excellent anti-HIV-1 wild strain activity,with ECso values ranging from 0.88 to 1.03 nM.Among all,SS-6c was found to be the most potent molecule,with an EC50 value of 0.88 nM against anti-HIV-1WT,which is better than the marketed drug zidovudine and is equivalent to the rilpivirine.The IASs linked to the NCp7 pharmacophore showed slightly weaker activity,with EC50 values ranging from 64.75-446.22 nM and is maybe due to the large molecular weight of the compound and poor membrane permeability after connecting the NCp7 pharmacophore.In addition,SS-6c(IC50=1.16 μM)and SS-7f(IC50=1.92 μM)showed strong RT inhibitor activity,proving that this series of compounds can act on RT.Currently,the NCp7 inhibitory activity of these compounds is being tested.