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 lead to failure
treatment. Thus, the development of new anti-HIV drugs and new treatment regimens are necessary.
Objective:
The aim of this study is to study 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 were determined by 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 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 com-bination 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.
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-1 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.
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