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1.
Antiviral Res ; 49(2): 101-14, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11248362

ABSTRACT

A new class of substituted 2'-benzisothiazolone represented by PD 161374 was discovered with antiviral activity against retroviruses similar to previously described nucleocapsid inhibitor PD 159206 (DIBA-4). In T cell culture, the 50% inhibitory concentrations (EC(50)) of PD 161374 and PD 159206 were on average 2.5 microM (ranges of 1.2-13.5 microM) without any cytotoxic effect up to 100 microM. PD 161374 inhibited acute HIV infection and it was effective when added during the early phase of HIV infection. However, very modest effects were observed in chronically infected H9 cells and the HIV latency model line OM-10.1. Direct PCR analysis of infected cells demonstrated that PD 161374 delayed the appearance of completed HIV-cDNA products including 2LTR circles. Together all these results suggest that PD 161374 exerts its antiviral effect at pre-integration steps in the early phase of the virus life cycle. When combined with a protease inhibitor, PD 161374 did not show any antagonism and combination with a reverse transcriptase inhibitor (AZT) resulted in a synergistic effect.


Subject(s)
Anti-HIV Agents/pharmacology , HIV-1/drug effects , Thiazoles/pharmacology , Cell Line , Drug Therapy, Combination , HIV Infections/virology , HIV-1/physiology , Humans , Reverse Transcriptase Inhibitors/pharmacology , Thiazoles/chemistry , Virus Replication/drug effects , Zidovudine/pharmacology
2.
Bioorg Med Chem ; 6(10): 1707-30, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9839002

ABSTRACT

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 alpha-, beta- and gamma-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the alpha-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 beta- and gamma-amino acids, were found to possess better antiviral and therapeutic efficacies than the alpha-amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9 microM with a therapeutic index of > 50. Interestingly, 2,2'-dithiobisbenzamides derived from alpha-amino acids containing a protected acid function and polar side chains also exhibited very good antiviral activity.


Subject(s)
Amino Acids/chemistry , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Benzamides/chemistry , Capsid Proteins , Viral Proteins , Amino Acid Sequence , Anti-HIV Agents/metabolism , Capsid/chemistry , Capsid/drug effects , Gene Products, gag/chemistry , Gene Products, gag/drug effects , Humans , Mass Spectrometry/methods , Molecular Sequence Data , Sp1 Transcription Factor/metabolism , Structure-Activity Relationship , Zinc/chemistry , gag Gene Products, Human Immunodeficiency Virus
3.
Drug Des Discov ; 15(1): 49-61, 1997 May.
Article in English | MEDLINE | ID: mdl-9332831

ABSTRACT

Substituted 2,2'-dithiobisbenzamides and 2-benzisothiazolones were prepared and shown to possess low microM activity with high therapeutic indices against HIV-1, HIV-2 and SIV in cell culture. The mechanism of antiviral action was determined to be directed toward the nucleocapsid protein (NCp7), which contains two zinc fingers and plays vital roles in the viral life cycle. The "active sulfides" of this study cause the extrusion of zinc from these zinc fingers. Structure-activity relationships of the 2,2'-dithiobisbenzamides reveal that the disulfide bond and the ortho benzamide functional groups are essential for activity, with the best compounds having a carboxylic acid, carboxamide, or sulfonamide substituent. The 2-benzisothiazolones are formed from the disulfides both chemically and in vivo and their SAR mimics that of the 2,2'-dithiobisbenzamides. The antiviral activity of the disulfides may require cyclization to the isothiazolones. Two agents, PD 159206 and PD 161374, which showed good antiviral activity, physical properties, and excellent pharmacokinetics in mice, were selected for advanced studies.


Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Benzamides/chemistry , Benzamides/pharmacokinetics , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Alkylation , Animals , Benzamides/chemical synthesis , Cell Line , Disulfides/chemistry , Disulfides/pharmacology , HIV-1/drug effects , Humans , Mice , Nucleocapsid Proteins/drug effects , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thioamides/chemistry , Thioamides/pharmacology
4.
Bioorg Med Chem ; 5(3): 569-79, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9113335

ABSTRACT

As part of the National Cancer Institute's Drug Screening Program, a new class of antiretrovirals active against the human immunodeficiency virus HIV-1 has been identified, and the HIV-1 nucleocapsid protein NCp7 was proposed as the target of antiviral action. The 2,2'-dithiobis-[4'-(sulfamoyl)benzanilide] (3x) and the 2,2'-dithiobis(5-acetylamino)benzamide (10) represented the prototypic lead structures. A wide variety of 2,2'-dithiobisbenzamides were prepared and tested for anti-HIV-1 activity, cytotoxicity, and their ability to extrude zinc from the zinc fingers for NCp7. The structure-activity relationships demonstrated that the ability to extrude zinc from NCp7 resided in the 2,2'-dithiobisbenzamide core structure. The 3,3' and the 4,4' isomers were inactive. While many analogs based upon the core structure retained the zinc extrusion activity, the best overall anti-HIV-1 activity was only found in a narrow set of derivatives possessing carboxylic acid, carboxamide, or phenylsulfonamide functional groups. These functional groups were more important for reducing cytotoxicity than improving antiviral potency or activity vs NCp7. All of the compounds with antiviral activity also extruded zinc from NCp7. From this study several classes of low microM anti-HIV agents with simple chemical structures were identified as possible chemotherapeutic agents for the treatment of AIDS.


Subject(s)
Anti-HIV Agents/chemical synthesis , Benzamides/chemical synthesis , Capsid Proteins , Capsid/drug effects , Gene Products, gag/drug effects , Viral Proteins , Zinc Fingers , Anti-HIV Agents/pharmacology , Benzamides/pharmacology , Humans , Structure-Activity Relationship , gag Gene Products, Human Immunodeficiency Virus
5.
Antimicrob Agents Chemother ; 41(2): 394-400, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9021197

ABSTRACT

It has been shown previously by our group and others that a series of four disulfide benzamides with cellular anti-human immunodeficiency virus (HIV) activity can eject zinc from HIV type 1 nucleocapsid protein (NCp7) in vitro while analogs without antiviral activity do not. We also found that the zinc ejection activity correlates with the loss of the ability of NCp7 to bind to HIV psi RNA in vitro. These observations indicate that the antiviral disulfide benzamides may act at a novel retroviral target of action, i.e., the nucleocapsid protein. The present studies examine the relationship among disulfide benzamide structure, in vitro NCp7 zinc ejection activity, and antiviral activity for a larger series of compounds. All of the antiviral disulfide benzamides were found to eject NCp7 zinc, while some disulfide benzamides with zinc ejection activity are not antiviral. Utilizing the thiol reagent 5,5'-dithiobis(2-nitrobenzoic acid), it was determined that the o-amido-phenyl disulfides being studied cyclize in aqueous solution to form benzisothiazolones. A series of benzisothiazolones, which are stable in solution in the absence of dithiothreitol, were found to eject NCp7 zinc at a rate similar to that of their disulfide benzamide analogs and to possess similar antiviral activity. It was also found that the relative rates of HIV inactivation by various disulfide benzamides and benzisothiazolones correlate with their relative kinetic rates of NCp7 zinc ejection, which is consistent with the nucleocapsid protein being the target of action of these compounds.


Subject(s)
Anti-HIV Agents/pharmacology , Benzamides/pharmacology , Capsid Proteins , Capsid/chemistry , Disulfides/pharmacology , Gene Products, gag/chemistry , HIV-1/drug effects , Thiazoles/pharmacology , Viral Proteins , Zinc Fingers , Zinc/chemistry , Anti-HIV Agents/chemistry , Benzamides/chemistry , Cytopathogenic Effect, Viral , Disulfides/chemistry , Humans , Kinetics , Structure-Activity Relationship , Thiazoles/chemistry , gag Gene Products, Human Immunodeficiency Virus
6.
J Med Chem ; 39(21): 4313-20, 1996 Oct 11.
Article in English | MEDLINE | ID: mdl-8863808

ABSTRACT

HIV nucleocapsid protein (NCp7) has been suggested as a possible target for 2,2'-dithiobis-[benzamide] and benzisothiazolone agents that inhibit viral replication in infected cells (Rice et al. Science 1995, 270, 1194-1197). The solution behavior of these compounds and the mechanistic events leading to removal of Zn from HIV nucleocapsid protein in vitro has been studied by electrospray ionization mass spectrometry, 500 MHz one- and two-dimensional nuclear magnetic resonance spectroscopy, and circular dichroism spectroscopy. We demonstrate that (1) Zn ejection is accompanied by formation of covalent complexes formed between the 2,2'-dithiobis[benzamide] monomers and Cys residues of Zn-depleted NCp7, (2) the rate of Zn ejection is faster for the C-terminal Zn finger and slower for the N-terminal finger, (3) Zn ejection results in a loss of structural integrity of the NCp7 protein, and (4) there is no appreciable interaction between a nonreactive isostere of the lead 2,2'-dithiobis[benzamide] and NCp7 in buffered aqueous solution. These findings are discussed in terms of the mechanism of action of Zn ejection by aromatic 2,2'-dithiobis[benzamides].


Subject(s)
Anti-HIV Agents/pharmacology , Benzamides/pharmacology , Capsid Proteins , Capsid/drug effects , Disulfides/pharmacology , Gene Products, gag/drug effects , Thiazoles/pharmacology , Viral Proteins , Zinc Fingers , Amino Acid Sequence , Anti-HIV Agents/chemistry , Benzamides/chemistry , Circular Dichroism , Disulfides/chemistry , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Sequence Data , Protein Conformation , Solutions , Thiazoles/chemistry , gag Gene Products, Human Immunodeficiency Virus
7.
Proc Natl Acad Sci U S A ; 93(3): 969-73, 1996 Feb 06.
Article in English | MEDLINE | ID: mdl-8577770

ABSTRACT

Several disulfide benzamides have been shown to possess wide-spectrum antiretroviral activity in cell culture at low micromolar to submicromolar concentrations, inhibiting human immunodeficiency virus (HIV) type 1 (HIV-1) clinical and drug-resistant strains along with HIV-2 and simian immunodeficiency virus [Rice, W. G., Supko, J. G., Malspeis, L., Buckheit, R. W., Jr., Clanton, D., Bu, M., Graham, L., Schaeffer, C. A., Turpin, J. A., Domagala, J., Gogliotti, R., Bader, J. P., Halliday, S. M., Coren, L., Sowder, R. C., II, Arthur, L. O. & Henderson, L. E. (1995) Science 270, 1194-1197]. Rice and coworkers have proposed that the compounds act by "attacking" the two zinc fingers of HIV nucleocapsid protein. Shown here is evidence that low micromolar concentrations of the anti-HIV disulfide benzamides eject zinc from HIV nucleocapsid protein (NCp7) in vitro, as monitored by the zinc-specific fluorescent probe N-(6-methoxy-8-quinoyl)-p-toluenesulfonamide (TSQ). Structurally similar disulfide benzamides that do not inhibit HIV-1 in culture do not eject zinc, nor do analogs of the antiviral compounds with the disulfide replaced with a methylene sulfide. The kinetics of NCp7 zinc ejection by disulfide benzamides were found to be nonsaturable and biexponential, with the rate of ejection from the C-terminal zinc finger 7-fold faster than that from the N-terminal. The antiviral compounds were found to inhibit the zinc-dependent binding of NCp7 to HIV psi RNA, as studied by gel-shift assays, and the data correlated well with the zinc ejection data. Anti-HIV disulfide benzamides specifically eject NCp7 zinc and abolish the protein's ability to bind psi RNA in vitro, providing evidence for a possible antiretroviral mechanism of action of these compounds. Congeners of this class are under advanced preclinical evaluation as a potential chemotherapy for acquired immunodeficiency syndrome.


Subject(s)
Antiviral Agents/pharmacology , Benzamides/pharmacology , Capsid/metabolism , Disulfides/pharmacology , HIV-1/metabolism , Viral Core Proteins/metabolism , Zinc/metabolism , Amino Acid Sequence , Aminoquinolines , Capsid/drug effects , Cloning, Molecular , Fluorescent Dyes , HIV-1/drug effects , Humans , Kinetics , Molecular Sequence Data , Recombinant Proteins/drug effects , Recombinant Proteins/metabolism , Structure-Activity Relationship , Tosyl Compounds , Tryptophan , Viral Core Proteins/drug effects
8.
Science ; 270(5239): 1194-7, 1995 Nov 17.
Article in English | MEDLINE | ID: mdl-7502043

ABSTRACT

Strategies for the treatment of human immunodeficiency virus-type 1 (HIV-1) infection must contend with the obstacle of drug resistance. HIV-1 nucleocapsid protein zinc fingers are prime antiviral targets because they are mutationally intolerant and are required both for acute infection and virion assembly. Nontoxic disulfide-substituted benzamides were identified that attack the zinc fingers, inactivate cell-free virions, inhibit acute and chronic infections, and exhibit broad antiretroviral activity. The compounds were highly synergistic with other antiviral agents, and resistant mutants have not been detected. Zinc finger-reactive compounds may offer an anti-HIV strategy that restricts drug-resistance development.


Subject(s)
Antiviral Agents/pharmacology , Benzamides/pharmacology , Capsid Proteins , Capsid/metabolism , Disulfides/pharmacology , Gene Products, gag/antagonists & inhibitors , HIV-1/drug effects , Viral Proteins , Zinc Fingers/drug effects , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Benzamides/chemistry , Benzamides/pharmacokinetics , Biological Availability , Capsid/chemistry , Cell Line , Disulfides/chemistry , Disulfides/pharmacokinetics , Drug Resistance, Microbial , Drug Synergism , Gene Products, gag/chemistry , HIV-1/physiology , Humans , Male , Mice , Molecular Sequence Data , gag Gene Products, Human Immunodeficiency Virus
9.
J Med Chem ; 38(22): 4478-87, 1995 Oct 27.
Article in English | MEDLINE | ID: mdl-7473575

ABSTRACT

A series of 1-cyclopropyl-6-fluoro-8-alkoxy (8-methyoxy and 8-ethoxy)-quionoline-3-carboxylic acids and 1-cyclopropyl-5-amino-6-fluoro-8-alkoxyquinoline-3-carboxylic acids has been prepared and evaluated for antibacterial activity. In addition, they were also compared to quinolones with classic substitution at C8 (H, F, Cl) and the naphthyridine nucleus in a phototoxicity and mammalian cell cytotoxicity assay. The series of 8-methoxyquinolones had antibacterial activity against Gram-positive, Gram-negative, and anaerobic bacteria equivalent to the most active 8-substituted compounds (8-F and 8-Cl). There was also a concomitant reduction in several of the potential side effects (i.e., phototoxicity and clonogenicity) compared to the most active quinolones with classic substitution at C-8. The 8-ethoxy derivatives had an even better safety profile but were significantly less active (2-3 dilutions) in the antibacterial assay.


Subject(s)
Anti-Bacterial Agents/pharmacology , Quinolones/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Bacteria/drug effects , CHO Cells , Cricetinae , Dermatitis, Phototoxic , Drug Design , Female , Mice , Mice, Inbred Strains , Microbial Sensitivity Tests , Quinolones/chemical synthesis , Quinolones/toxicity , Structure-Activity Relationship
10.
J Med Chem ; 35(2): 361-7, 1992 Jan 24.
Article in English | MEDLINE | ID: mdl-1732554

ABSTRACT

A series of 8-(trifluoromethyl)-substituted quinolones has been prepared and evaluated for in vitro and in vivo antibacterial activity, and phototolerance in a mouse phototolerance assay. These analogues were compared to the corresponding series of 6,8-difluoro- and 6-fluoro-8H-quinolones (ciprofloxacin type). Although their in vitro antibacterial activities are less than the 6,8-difluoro analogues, the 8-(trifluoromethyl)quinolones are generally equivalent to their 8H analogues. In vivo, they are comparable to the 6,8-difluoro series and show up to 10-fold improvement in efficacy when compared to their ciprofloxacin counterparts vs Streptococcus pyogenes and Streptococcus pneumonia. In the phototolerance model, the 8-(trifluoromethyl)quinolones are comparable to the 8H-quinolones. Both of these series display much higher no effect doses (greater tolerance) than the corresponding 6,8-difluoroquinolones.


Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/toxicity , Photosensitivity Disorders/chemically induced , 4-Quinolones , Administration, Oral , Animals , Anti-Infective Agents/pharmacology , Bacterial Infections/drug therapy , Female , Injections, Subcutaneous , Mice , Microbial Sensitivity Tests , Structure-Activity Relationship
11.
J Med Chem ; 34(2): 656-63, 1991 Feb.
Article in English | MEDLINE | ID: mdl-1995890

ABSTRACT

A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.2.1]octanes have been prepared and evaluated in vitro and in vivo for antibacterial activity against a variety of Gram-negative and Gram-positive organisms. These compounds were also tested against the target enzyme bacterial DNA gyrase. All the examples investigated are nearly equipotent with the parent 7-piperazinyl analogues. Only endo-7-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-1-cyclopropyl-6,8-difluoro- 1,4- dihydro-4-oxo-3-quinolinecarboxylic acid displays activity that surpasses that of the piperazine parent.


Subject(s)
Anti-Infective Agents/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Piperazines/chemical synthesis , 4-Quinolones , Animals , Anti-Infective Agents/pharmacology , Bridged Bicyclo Compounds/pharmacology , Chemical Phenomena , Chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Mice , Microbial Sensitivity Tests , Piperazines/pharmacology , Structure-Activity Relationship
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