219309-97-4

Upstream product

• 19602-82-5 2,2'-dithiodibenzoic acid dichloride 
• 4726-85-6 β-alaninamide 
• 64017-81-8 3-aminopropanamide hydrochloride 
• 497262-13-2 N,N'-disuccinimidyl-2,2'-dithiosalicylate 
• 147-93-3 Thiosalicylic acid 
• 252898-13-8 N^β-(2-mercaptobenzoyl)-β-alaninamide 

Downstream Products

• 252898-13-8 N^β-(2-mercaptobenzoyl)-β-alaninamide 
• 443882-51-7 (2-bromo-ethyl)-thiocarbamic acid S-[2-(2-carbamoyl-ethylcarbamoyl)-phenyl] ester 
• 1258516-83-4 N-{2-[4-(isopropylcarbonyl-oxy)benzylthio]benzoyl}-β-alaninamide 

Relevant academic research and scientific papers

Preclinical evaluation of a mercaptobenzamide and its prodrug for NCp7-targeted inhibition of human immunodeficiency virus

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.

Reaction Kinetics Direct a Rational Synthesis of an HIV-1 Inactivator of Nucleocapsid Protein 7 and Provide Mechanistic Insight into Cellular Metabolism and Antiviral Activity

Mercaptobenzamide thioester SAMT-247 is a non-toxic, mutation-resistant HIV-1 maturation inhibitor with a unique mechanism of antiviral activity. NMR spectroscopic analyses of model reactions that mimic the cellular environment answered fundamental questions about the antiviral mechanism and inspired a high-yielding (64 % overall), scalable (75 mmol), and cost-effective ($4 mmol?1) three-step synthesis that will enable additional preclinical evaluation.

N-(3-AMINO-3-OXOPROPYL)-2-[(1-METHYL-4-NITRO-1H-IMIDAZOL-5-YL)THIO]BENZAMIDE AND ITS USE FOR TREATING HIV INFECTION

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.

Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7

In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC50 = 42 nM) in MT-4 cells, and sub-micromole (EC50 = 0.308 μM) to inhibit HIV-1 NL4-3 strain in TZM-bl cells. This is a significant improvement over the parent drug MT. In addition, it showed moderate inhibitory potency (EC50 = 1.329 μM) against the HIV-1 K103N/Y181C double mutant strain (MT-4 cells). The metabolic stability in human plasma of compound 7c indicated that it can release the active forms of the parent drugs MT and AZT in a linear time-independent manner and turn out to be a potential prodrug.

2-mercaptobenzamide thioester compound and preparation method therefor and application of 2-mercaptobenzamide thioester compound

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).

A one-pot preparation of N-2-mercaptobenzoyl-amino amides

The HIV-1 nucleocapsid (NCp7), structurally defined by zinc-binding domains, participates in crucial stages of the HIV-1 lifecycle and is mutationally nonpermissive, making it an attractive anti-HIV target. Mode of action studies have shown that the secondary structure and activity of NCp7 can be disrupted by acyl transfer from N-2-mercaptobenzoyl-amino amides. We have developed an improved one-pot reaction that affords N-2-mercaptobenzoyl-amino acids on multi-gram scales. This synthetic route allows for rapid modular construction and has greatly expanded the scope of easily accessible potential NCp7 inhibitors.

Optimization of unique, uncharged thioesters as inhibitors of HIV replication

Synthesis and antiviral activity of uncharged thioesters is described. A combinatorial chemistry approach was employed to prepare a restricted library of N-substituted S-acyl-2-mercaptobenzamide thioesters. It was shown that many members of this chemotype display anti-HIV activity via their ability to interact with HIV-1, HIV-2, SIV-infected cells, cell-free virus, and chronically and latently infected cells in a manner consistent with targeting of the highly conserved HIV-1 NCp7 zinc fingers. Compounds were initially screened using two different in vitro antiviral assays and evaluated for stability in neutral buffer containing 10% pooled human serum using a spectrophotometric assay. These data revealed that there was no significant correlation between thioester stability and antiviral activity, however, a slight inverse correlation between serum stability and virucidal activity was noted. Based on the virucidal capability and the ability to select lead compounds to inhibit virus expression from latently infected TNFα-induced U1 cells, we next determined if these compounds could prevent HIV cell-to-cell transmission. Several thioesters demonstrated potent inhibition of HIV cell-to-cell transmission with EC 50 values in the 80-100 nM range. Thus, we have optimized a series of restricted thioesters and provided evidence that serum stability is not required for antiviral activity. Moreover, selected compounds show potential for development as topical microbicides.

Benzamide-based thiolcarbamates: A new class of HIV-1 NCp7 inhibitors

The HIV-1 nucleocapsid protein NCp7, which contains two highly conserved zinc fingers, is being used as a novel target for AIDS therapy due to its pivotal role in viral replication and its mutationally intolerant nature. Herein we report a new class of NC

2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids possessing anti-HIV activities: Synthesis and structure-activity relationship

Nucleocapsid protein (NCp7), which contains highly conserved retroviral zinc fingers, is essential in the early as well as the late phase of human immunodeficiency virus (HIV) life cycle and constitutes a novel target for AIDS therapy. HIV-1 NCp7 is a basic 55 amino acid protein containing two C(X)2C(X)4H(X)4C motif zinc fingers flanked by basic amino acids on each side. 2,2'-dithiobisbenzamides have previously been reported to release zinc from these NCp7 zinc fingers and also to inhibit HIV replication. Specifically, 2,2'-dithiobisbenzamides derived from simple amino acids showed good antiviral activities. The benzisothiazolone 3, the cyclic derivative of 2, was selected for clinical trials as an agent for AIDS therapy. Herein we report the syntheses and antiviral activities, including therapeutic indices, of 2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the α-amino acid derived 2,2'-dithiobisbenzamides, analogues containing alkyl side chains were found to be antivirally active with good therapeutic indices. 2,2'-Dithiobisbenzamides, derived from β- and γ-amino acids, were found to possess better antiviral and therapeutic efficacies than the α-amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9μM with a therapeutic index of >50. Interestingly, 2,2'-dithiobisbenzamides derived from α-amino acids containing a protected acid function and polar side chains also exhibited very good antiviral activity. Copyright (C) 1998 Elsevier Science Ltd.