219309-97-4Relevant articles and documents
Preclinical evaluation of a mercaptobenzamide and its prodrug for NCp7-targeted inhibition of human immunodeficiency virus
Hartman,Yang,Helfrick,Hassink,Shank,George Rosenker,Scerba,Saha,Hughes,Wang,Xu,Gupta,Buckheit,Appella
, p. 216 - 225 (2016)
Although the effective use of highly active antiretroviral therapy results in the suppression of virus production in infected individuals, it does not eliminate the infection and low level virus production in cells harboring virus in sanctuary sites. Thus, the continued search for new antiretroviral agents with unique and different mechanisms of HIV inhibition remains critical, and compounds that can reduce the level of virus production from cells already infected with HIV, as opposed to preventing de novo infection, would be of great benefit. A mercaptobenzamide (MDH-1-38) and its prodrug (NS1040) are being developed as potential therapeutic compounds targeting the zinc finger of HIV nucleocapsid. In the presence of esterase enzymes, NS1040 is designed to be converted to MDH-1-38 which has antiviral activity. While we presume that NS1040 is rapidly converted to MDH-1-38 in all experiments, the two compounds were tested side-by-side to determine whether the presence of a prodrug affects the antiviral activity or mechanism of action. The two compounds were evaluated against a panel of HIV-1 clinical isolates in human PBMCs and monocyte-macrophages and yielded EC50 values ranging from 0.7 to 13?μM with no toxicity up to 100?μM. MDH-1-38 and NS1040 remained equally active in human PBMCs in the presence of added serum proteins as well as against HIV-1 isolates resistant to reverse transcriptase, integrase or protease inhibitors. Cell-based and biochemical mechanism of antiviral action assays demonstrated MDH-1-38 and NS1040 were virucidal at concentrations of 15 and 50?μM, respectively. Cell to cell transmission of HIV in multiple passages was significantly reduced in CEM-SS and human PBMCs by reducing progeny virus infectivity at compound concentrations greater than 2?μM. The combination of either MDH-1-38 or NS1040 with other FDA-approved HIV drugs yielded additive to synergistic antiviral interactions with no evidence of antiviral antagonism or synergistic toxicity. Serial dose escalation was used in attempts to select for HIV strains resistant to MDH-1-38 and NS1040. Virus at several passages failed to replicate in cells treated at increased compound concentrations, which is consistent with the proposed mechanism of action of the virus inactivating compounds. Through 14 passages, resistance to the compounds has not been achieved. Most HIV inhibitors with mechanism of antiviral action targeting a viral protein would have selected for a drug resistant virus within 14 passages. These studies indicate that these NCp7-targeted compounds represent new potent anti-HIV drug candidates which could be effectively used in combination with all approved anti-HIV drugs.
N-(3-AMINO-3-OXOPROPYL)-2-[(1-METHYL-4-NITRO-1H-IMIDAZOL-5-YL)THIO]BENZAMIDE AND ITS USE FOR TREATING HIV INFECTION
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Paragraph 0137-0139, (2021/06/26)
Disclosed is a compound of formula (I): for treating or preventing a human immunodeficiency virus (HIV) infection in a mammal, for inhibiting or preventing maturation of an immature human immunodeficiency virus (HIV) to a mature HIV, and for preventing or inhibiting a human immunodeficiency virus (HIV) infection in a mammal having at least one HIV viral particle on a surface thereof.
2-mercaptobenzamide thioester compound and preparation method therefor and application of 2-mercaptobenzamide thioester compound
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Paragraph 0032-0033, (2020/09/20)
The invention relates to a 2-mercaptobenzamide thioester double-target prodrug and a preparation method therefor and application of the double-target prodrug. The general structural formula of the compound is as shown in the specification; in the formula, linker is ethyl, propyl, n-butyl, isobutyl and neopentyl. The invention further provides application of the compound and a composition containing one or more compounds to preparation of drugs for treating and preventing a human immunodeficiency virus (HIV).
