C6-structural optimizations of 2-aryl-1H-pyrazole-S-DABOs: From anti-HIV to anti-DENV activity.

Both HIV and DENV are serious threats to human life, health and social economy today. So far, no vaccine for either HIV or DENV has been developed successfully. The research on anti-HIV or DENV drugs is still of great significance. In this study we developed a series of novel 2-Aryl-1H-pyrazole-S-DABOs with C6-strucutral optimizations as potent NNRTIs, among which, 8 compounds had low cytotoxicity and EC50 values in the range of 0.0508 âˆ¼ 0.0966 µM, and their selectivity index was SI > 1415 âˆ¼ 3940. In particular, two compounds 4a and 4b were identified to have good inhibitory effects on DENV of four serotypes. The EC50 of compound 4a and 4b against DENV-II (13.2 µM and 9.23 µM, respectively) were better than that of the positive control ribavirin (EC50 = 40.78 µM). In addition, the effect of C-6 substituents on the anti-HIV or anti-DENV activity of these compounds was also discussed.

Chemoselective synthesis of isolated and fused fluorenones and their photophysical and antiviral properties.

Highly functionalized fluorenones were synthesized by an intramolecular cyclization of 2''-halo-[1,1':3',1''-terphenyl]-4'-carbonitriles in the presence of n-butyllithium or lithium aluminium hydride. The precursor was synthesized by ring transformation of 2-oxo-6-aryl/heteroaryl-4-(sec.amino)-2H-pyran-3-carbonitriles or 2-oxobenzo[h]chromenes with o-bromo/chloro/fluoro-acetophenone under basic conditions in moderate yield. We performed the control experiment to understand the proposed mechanism and found that the presence of a secondary amine in the starting material directs the reactivity. The photophysical properties of 3-methoxy-7-(piperidin-1-yl)-5H-indeno[2,1-b]phenanthren-8(6H)-one was explored and solvent dependent emission was observed. These compounds were also tested against HIV-1 and low to moderate activity was observed.

Hit optimization studies of 3-hydroxy-indolin-2-one analogs as potential anti-HIV-1 agents.

In the current study, twenty-two compounds based upon 3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one nucleus were designed, synthesized and in vitro evaluated for HIV-1 RT inhibition and anti-HIV-1 activity. Compounds 3d, 5c and 5e demonstrated encouraging potency against RT enzyme as well as HIV-1 in low micromolar to nanomolar concentration with good to excellent safety index. Structure activity relationship studies revealed that halogens such as bromo or chloro at 5th the position of oxindole ring remarkably enhanced the potency against RT. Moreover, methoxy or chloro groups at the ortho position of phenyl ring also significantly favored RT inhibition activity. Seven compounds (3b, 3c, 3d, 3e, 5b, 5c and 5e) with better anti-HIV-1 potency were tested against the mutant HIV-1K103N strain. The putative binding mode, as well as interaction patterns of the best active compound 5c with wild HIV-1 RT were studied via docking studies.

Synthesis and study of anti-HIV-1 RT activity of 5-benzoyl-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one derivatives.

In the present study, a series of fourteen 5-benzoyl-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one derivatives were designed, synthesized and characterized by appropriate spectral analysis. Further, titled compounds were in-vitro screened against wild HIV-1 RT enzyme using ELISA based colorimetric assay, in which four compounds significantly inhibited the RT activity with IC50≤25µM. Moreover, two significantly active compounds of the series, A10 and A11 exhibited IC50 values 8.62 and 6.87µM respectively, during the in-vitro assay. Structure Activity Relationship (SAR) studies were performed for the synthesized compounds in order to estimate the effect of substitution pattern on the RT inhibitory potency. The cytotoxicity of the synthesized compounds was evaluated against T lymphocytes. Further, putative binding modes of the significantly active (A11) and the least active (A4) compounds with wild HIV-1 RT were also investigated using docking studies.

[The anti-HIV-1 activities of benzophenones non-nucleoside reverse transcriptase inhibitors in vitro].

To evaluate the anti-HIV-1 activities of 5 benzophenones non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as DY1203, DY1204, DY1119, DY1208 and DY1209 in vitro, the cytotoxicity of 5 compounds were tested on C8166, MT-4, H9 and PBMC with the MTT assay. The anti-HIV-1 activities of compounds were evaluated on laboratory-adapted strain, drug-resistant strains and primary isolated strains by p24 antigen expression ELISA. The inhibition of HIV-1 recombinant reverse transcriptase activity was assessed by ELISA assay. Among 5 compounds, DY1203 and DY1204 showed low cytotoxicities with CC(50) greater than 200 µg·m L(-1). DY1119, DY1208 and DY1209 showed strong anti-HIV-1 activities against HIV-1(IIIB,) HIV-1(74V,) HIV-1(RF/V82F/184V,) HIV-1(NL4-3) (gp41(36G)N42S,) HIV-1(KM018,) HIV-1(TC-1) and HIV-1(Wan.) However, NNRTIs drug-resistant strain HIV-1(A17) showed different resistance to these compounds. The 5 compounds proved active against HIV-1 recombinant reverse transcriptase. DY1208 is expected to become a new lead compound for its high therapeutic index. The results can provide new information for HIV-1 drug research and promote the development of new HIV-1 drugs.

The New NNRTI ACC007 Combined with Lamivudine and Tenofovir Disoproxil Fumarate Show Synergy Anti-HIV Activity In Vitro.

BACKGROUND: Acquired immunodeficiency syndrome can hardly be cured currently and people with human immunodeficiency virus (HIV) need lifelong treatment that may result in the emergence of drug resistance which leads to failed treatment. Thus, the development of new anti- HIV drugs and new treatment regimens are necessary. OBJECTIVE: The aim of this study is to analyze the combined anti-HIV activity of tenofovir disoproxil fumarate, lamivudine and ACC007, a new non-nucleoside reverse transcriptase inhibitor. METHODS: The antiviral activity of tenofovir disoproxil fumarate, lamivudine and ACC007 alone or in combination against different HIV-1 strains was determined by the detection of HIV-1 p24 level through enzyme-linked immunosorbent assay. RESULT: ACC007 showed EC50 of nanomolar range (from 3.03 nM to 252.59 nM) against all HIV-1 strains used in this study except the HIV-1A17, with EC50 of 1.57 µM. The combined antiviral activity of ACC007, lamivudine and tenofovir disoproxil fumarate showed synergy antiviral activity against all HIV-1 strains used in this study. The three-drug combination showed moderate synergism against HIV-1A17, HIV-14755-5, HIV-1K103N and HIV-1V106M, with a combination index value ranging from 0.71 to 0.87, and showed synergism against the other HIV-1 strains with combination index value from 0.35 to 0.67. The combination with ACC007 significantly increases the dose reduction index value of lamivudine and tenofovir disoproxil fumarate, compared with two-drug combination. CONCLUSION: ACC007 exhibits potent antiviral activity alone or with 3TC and TDF, and exerts synergistic effect against all HIV strains used in our investigation in vitro.