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1.
Curr Top Med Chem ; 14(17): 2031-41, 2014.
Article in English | MEDLINE | ID: mdl-25322771

ABSTRACT

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.


Subject(s)
Antineoplastic Agents/chemical synthesis , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Thiazoles/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Models, Molecular , Molecular Docking Simulation , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Thiazoles/pharmacology
2.
Curr Top Med Chem ; 14(17): 2020-30, 2014.
Article in English | MEDLINE | ID: mdl-25262797

ABSTRACT

A tremendous research on Poly (ADP-ribose) polymerase (PARP) pertaining to cancer and ischemia is in very rapid progress. PARP's are a specific class of enzymes that repairs the damaged DNA. Recent findings suggest also that PARP-1 is the most abundantly expressed nuclear enzyme which involves in various therapeutic areas like inflammation, stroke, cardiac ischemia, cancer and diabetes. The current review describes the overview on clinical candidates of PARP1 and its current status in clinical trials. This paper also covers identification of potent PARP1 inhibitors using structure and ligand based pharmacophore models. Finally 36 potential hits were identified from the virtual screening of pharmacophore models and screened for PARP1 activity. 15 actives were identified as potent PARP1 inhibitors and further optimization of these analogues are in progress.


Subject(s)
Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Clinical Trials as Topic , Enzyme Inhibitors/therapeutic use , Humans , Molecular Docking Simulation , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerase Inhibitors
3.
Curr Top Med Chem ; 14(17): 1977-89, 2014.
Article in English | MEDLINE | ID: mdl-25262802

ABSTRACT

Anthrax Lethal Factor (LF) is a zinc-dependent metalloprotease, one of the virulence factor of anthrax infection. Three forms of the anthrax infection have been identified: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). Anthrax toxin is composed of protective antigen (PA), lethal factor (LF), and edema factor (EF). Protective antigen mediates the entry of Lethal Factor/Edema Factor into the cytosol of host cells. Lethal factor (LF) inactivates mitogen-activated protein kinase kinase inducing cell death, and EF is an adenylyl cyclase impairing host defenses. In the past few years, extensive studies are undertaken to design inhibitors targeting LF. The current review focuses on the small molecule inhibitors targeting LF activity and its structure activity relationships (SAR).


Subject(s)
Anthrax/drug therapy , Antigens, Bacterial/metabolism , Bacillus anthracis/growth & development , Bacterial Toxins/metabolism , Mitogen-Activated Protein Kinase Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Animals , Antigens, Bacterial/chemistry , Bacillus anthracis/enzymology , Bacterial Toxins/chemistry , Humans , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Models, Molecular , Protein Kinase Inhibitors/therapeutic use , Rats , Structure-Activity Relationship
4.
Org Biomol Chem ; 11(29): 4778-91, 2013 Aug 07.
Article in English | MEDLINE | ID: mdl-23778751

ABSTRACT

Novel quinazolinone based α-glucosidase inhibitors have been developed. For this purpose a virtual screening model has been generated and validated utilizing acarbose as a α-glucosidase inhibitor. Homology modeling, docking, and virtual screening were successfully employed to discover a set of structurally diverse compounds active against α-glucosidase. A search of a 3D database containing 22,500 small molecules using the structure based virtual model yielded ten possible candidates. All ten candidates were N-3-pyridyl-2-cyclopropyl quinazolinone-4-one derivatives, varying at the 6 position. This position was modified by Suzuki-Miyaura cross coupling with aryl, heteroaryl, and alkyl boronic acids. A catalyst screen was performed, and using the best optimal conditions, a series of twenty five compounds was synthesized. Notably, the C-C cross coupling reactions of the 6-bromo-2-cyclopropyl-3-(pyridyl-3-ylmethyl)quinazolin-4(3H)-one precursor have been accomplished at room temperature. A comparison of the relative reactivities of 6-bromo and 6-chloro-2,3-disubstituted quinazolinones with phenyl boronic acid was conducted. An investigation of pre-catalyst loading for the reaction of the 6-bromo-2-cyclopropyl-3-(pyridyl-3-ylmethyl)quinazolin-4(3H)-one substrate was also carried out. Finally, we submitted our compounds to biological assays against α-glucosidase inhibitors. Of these, three hits (compounds 4a, 4t and 4r) were potentially active as α-glucosidase inhibitors and showed activity with IC50 values <20 µM. Based on structural novelty and desirable drug-like properties, 4a was selected for structure-activity relationship study, and thirteen analogs were synthesized. Nine out of thirteen analogs acted as α-glucosidase inhibitors with IC50 values <10 µM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.


Subject(s)
Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors , Quinazolinones/pharmacology , Temperature , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Quinazolinones/chemical synthesis , Quinazolinones/chemistry , Structure-Activity Relationship , alpha-Glucosidases/metabolism
5.
Curr Pharm Des ; 19(4): 687-701, 2013.
Article in English | MEDLINE | ID: mdl-23016864

ABSTRACT

Fibroblast growth factor receptors (FGFRs) play an important role in embryonic development, angiogenesis, wound healing, cell proliferation and differentiation. The fibroblast growth factor receptor (FGFR) isoforms have been under intense scrutiny for effective anticancer drug candidates. The fibroblast growth factor (FGF) and its receptor (FGFR) provide another pathway that seems critical to monitoring angiogenesis. Recent findings suggest that FGFR mediates signaling, regulates the PKM2 activity, and plays a crucial role in cancer metabolism. The current review also covers the recent findings on the role of FGFR1 in cancer metabolism. This paper reviews the progress, mechanism, and binding modes of recently known kinase inhibitors such as PD173074, SU series and other inhibitors still under clinical development. Some of the structural classes that will be highlighted in this review include Pyrido[2,3-d]pyrimidines, Indolin- 2-one, Pyrrolo[2,1-f][1,2,4]triazine, Pyrido[2,3-d]pyrimidin-7(8H)-one, and 1,6- Naphthyridin-2(1H)-ones.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Angiogenesis Inhibitors/pharmacology , Animals , Humans , Neoplasms/blood supply , Neoplasms/drug therapy , Neoplasms/metabolism , Neovascularization, Pathologic/drug therapy , Neovascularization, Physiologic , Protein Isoforms , Pyrimidines/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Receptors, Fibroblast Growth Factor/metabolism , Signal Transduction
6.
J Mol Graph Model ; 29(2): 256-65, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20727800

ABSTRACT

Bacillus anthracis is a causative organism of anthrax. The main reason to use anthrax as a bioweapon is the combination of the spore's durability and the lethal toxaemia of the vegetative stage. In anthrax infection, lethal factor (LF) is playing crucial role in causing cell death, by inhibiting pathways that rely on this kinase family. The combination of vaccine and antibiotics is preferred as an effective treatment for this target. Till date, no small molecule inhibitor is identified as a drug on the target. In this study, we have performed pharmacophore modeling and docking studies to identify a novel small molecule inhibitor to target the Anthrax LF. The best pharmacophore model is used to screen approximately 2M drug-like small molecule database and yielded 2543 hits. Docking studies of the pharmacophore hits on to the active site of Anthrax LF resulted 120 structurally diverse hits. Out of 120 hits, based on synthetic feasibility, 17 hits are selected for further synthesis and pharmacological screening. In due course, we will publish the updated results.


Subject(s)
Antitoxins/chemistry , Antitoxins/pharmacology , Bacterial Toxins/antagonists & inhibitors , Drug Design , Drug Evaluation, Preclinical , Models, Molecular , User-Computer Interface , Antigens, Bacterial/chemistry , Bacterial Toxins/chemistry , Catalytic Domain , Crystallography, X-Ray , Ligands , Molecular Conformation
7.
J Mol Graph Model ; 28(6): 472-7, 2010 Feb 26.
Article in English | MEDLINE | ID: mdl-20005756

ABSTRACT

Heat Shock Protein 90 (HSP90), an ATP-dependent molecular chaperone, has emerged as a promising target in the treatment of cancer. Inhibition of HSP90 represents a new target of antitumor therapy, since it may influence many specific signaling pathways. Many HSP90 inhibitors bind to the ATP-binding pocket, inhibit chaperone function, resulting in cell death. Recent clinical trials for treatment of cancer have put HSP90's importance into focus and have highlighted the need for full scale research into HSP90 related pathways. Here we report five novel HSP90 inhibitors which were identified by using pharmacophore models and docking studies. We used highly discriminative pharmacophore model as a 3D query to search against database of approximately 1 M compounds and cluster analysis results yielded 455 compounds which were further subjected for docking. Glide docking studies suggested 122 compounds as in silico hits and these compounds were further selected for the cytotoxicity assay in the HSP90-over expressing SKBr3 cell line. Of the 122 compounds tested, 5 compounds inhibited cell growth with an IC(50) value less than 50 microM.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Models, Molecular , Cell Death/drug effects , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Humans , Reproducibility of Results
8.
Bioorg Med Chem ; 17(7): 2925-35, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19026554

ABSTRACT

Previously, we discovered linomide analogues as novel HIV-1 integrase (IN) inhibitors. Here, to make possible structure-activity relationships, we report on the design and synthesis of a series of substituted dihydroquinoline-3-carboxylic acids. The crystal structure of the representative compound 2c has also been solved. Among the eight new analogues, 2e showed a potency in inhibiting IN strand transfer catalytic activity similar to the reference diketo acid inhibitor L-731,988 (IC(50)=0.9 microM vs. 0.54 microM, for 2e and L-731,988, respectively). Furthermore, none of the compounds showed significant cytotoxicity in two tested cancer cell lines. These compounds represent an interesting prototype of IN inhibitors, potentially involved in a metal chelating mechanism, and further optimization is warranted.


Subject(s)
Carboxylic Acids/chemical synthesis , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/chemistry , Quinolines/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/toxicity , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/toxicity , Humans , Inhibitory Concentration 50 , Molecular Conformation , Quinolines/chemistry , Quinolines/toxicity , Structure-Activity Relationship
9.
J Med Chem ; 52(1): 20-32, 2009 Jan 08.
Article in English | MEDLINE | ID: mdl-19072053

ABSTRACT

Human apurinic/apyrimidinic endonuclease 1 (APE1) is an important enzyme in the base excision repair (BER) pathway that is essential for the repair of abasic sites in the genome. Evidence for APE1 as an attractive therapeutic target in anticancer drug development has been demonstrated by studies that link overexpression of APE1 in many cancers to resistance of tumor cells to radio- and chemotherapy. APE1 also shows a protective effect in several cancer cell models to a variety of DNA damaging agents. This study represents the first rational design of selective small-molecule APE1 inhibitors utilizing a three-dimensional interaction-based pharmacophore perception. All of our most potent molecules show inhibitory activity below 10 muM and are selective for APE1 inhibition.


Subject(s)
DNA-(Apurinic or Apyrimidinic Site) Lyase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Biocatalysis , Combinatorial Chemistry Techniques , Crystallography, X-Ray , DNA/chemistry , DNA/metabolism , DNA-(Apurinic or Apyrimidinic Site) Lyase/chemistry , DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism , Drug Design , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity Relationship
10.
Bioorg Med Chem ; 16(16): 7777-87, 2008 Aug 15.
Article in English | MEDLINE | ID: mdl-18644730

ABSTRACT

Aryl diketoacids (ADK) and their bioisosteres are among the most promising HIV-1 integrase (IN) inhibitors. Previously, we designed a series of ADK dimers as a new class of IN inhibitors that were hypothesized to target two divalent metal ions on the active site of IN. Herein we present a further structure-activity relationship (SAR) study with respect to the substituent effect of the ADK and the dimerization with conformationally constrained linkers such as piperazine, 4-amino-piperidine, piperidin-4-ol, and trans-cyclohexan-1,4-diamine. The substituents on the phenyl ring as well as the spatial orientation of the two diketo units were observed to play important roles in the IN inhibitory potency. The hydrophobic group was an optimal substitution at the 3-position of the aryl ring. The piperazine and 4-amino-piperidine linkers brought about the most potent analogs among the hydrophobic group or halogen substituted ADK dimers. The docking studies suggested that the bulky hydrophobic substitution at 3-phenyl ring and the linker of 4-amino-piperidine were beneficial for adopting an active conformation to achieve strong interactions with the active site Mg(2+) and the key residue E152 within the catalytic core domain. This study is a significant extension of our previous report on the dimeric ADK-containing IN inhibitors, providing a new promising template for further lead optimization.


Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , Keto Acids/chemistry , Keto Acids/pharmacology , Dimerization , HIV Integrase/chemistry , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemical synthesis , Keto Acids/chemical synthesis , Mass Spectrometry , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Structure-Activity Relationship
11.
Virology ; 377(2): 355-63, 2008 Aug 01.
Article in English | MEDLINE | ID: mdl-18514248

ABSTRACT

HIV-1 integrase (IN) is an essential enzyme for viral infection. Here, we report an extensive pi electron orbital interaction between four amino acids, W132, M178, F181 and F185, located at the dimeric interface of IN that is critical for the strand transfer activity alone. Catalysis of nine different mutant IN proteins at these positions were evaluated. Whereas the 3'-processing activity is predominantly strong, the strand transfer activity of each enzyme was completely dependent on an intact pi electron orbital interaction at the dimeric interface. Four representative IN mutants were constructed in the context of the infectious NL4.3 HIV-1 viral clone. Whereas viruses with an intact pi electron orbital interaction at the IN dimeric interface replicated comparable to wild type, viruses containing an abolished pi interaction were non-infectious. Q-PCR analysis of viral DNA forms during viral replication revealed pleiotropic effects of most mutations. We hypothesize that the pi interaction is a critical contact point for the assembly of functional IN multimeric complexes, and that IN multimerization is required for a functional pre-integration complex. The rational design of small molecule inhibitors targeting the disruption of this pi-pi interaction should lead to powerful anti-retroviral drugs.


Subject(s)
HIV Integrase/physiology , HIV-1/pathogenicity , Virus Integration/physiology , DNA, Viral/analysis , Dimerization , Electrons , HIV Integrase/chemistry , HIV-1/genetics , Humans , Virus Integration/genetics
12.
J Med Chem ; 51(12): 3367-77, 2008 Jun 26.
Article in English | MEDLINE | ID: mdl-18500794

ABSTRACT

Consensus virtual screening models were generated and validated utilizing a set of known human epidermal growth factor receptor-2 (HER2) inhibitors and modeled HER2 active and inactive state structures. The virtual screening models were successfully employed to discover a set of structurally diverse compounds with growth inhibitory activity against HER2-overexpressing SKBR3 breast cancer cell line. A search of a 3D database containing 350000 small-molecules using the consensus models retrieved 531 potential hits. Of the 531 hits, 57 were selected for testing in SKBR3 cells on the basis of structural novelty and desirable drug-like properties. Seven compounds inhibited growth of SKBR3 cells with IC50 values <10 microM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.


Subject(s)
Antineoplastic Agents/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Amino Acid Sequence , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Breast Neoplasms , Catalytic Domain , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Ligands , Models, Molecular , Molecular Sequence Data , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Quantitative Structure-Activity Relationship , Quinazolines/chemical synthesis , Quinazolines/chemistry , Quinazolines/pharmacology , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Receptor, ErbB-2/biosynthesis , Small Molecule Libraries
13.
ChemMedChem ; 3(6): 986-90, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18383063

ABSTRACT

Two sets of compounds derived from the fusion of a diversely annulated naphthoxazepinedione system with 1,3-thiazole and 1,3-oxazole are described. These compounds are close analogues of previously reported thiazolothiazepine inhibitors of human immunodeficiency virus type 1 integrase (HIV-1 IN). Some of the new derivatives show potency similar to that of the reference compounds, thus gaining further insight into the structure-activity relationship of this class of IN inhibitors.


Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , HIV Integrase/drug effects , HIV-1/drug effects , Oxazepines/chemical synthesis , Oxazepines/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Design , HIV Integrase Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Oxazepines/chemistry , Stereoisomerism , Structure-Activity Relationship
14.
FEBS Lett ; 582(10): 1425-30, 2008 Apr 30.
Article in English | MEDLINE | ID: mdl-18331842

ABSTRACT

A lens epithelium-derived growth factor (LEDGF)/p75 peptide was evaluated for human immunodeficiency virus type 1 integrase (IN) inhibitory activity. The LEDGF/p75 peptide modestly inhibited IN catalysis and was dependent on IN-DNA assembly. The peptide was also effective at disrupting LEDGF/p75-IN complex formation. We next investigated the activity of the LEDGF/p75 peptide on IN mutant proteins that are unable to catalyze the DNA strand transfer reaction. The LEDGF/p75 peptide displayed an increased potency on these IN proteins, from 5-fold to greater than 10-fold, indicating the IN multimeric state greatly influences the peptide inhibitory effects. These results shed light on IN-DNA multimeric formation, and how this process influences the LEDGF/p75-IN interaction.


Subject(s)
HIV Integrase Inhibitors/pharmacology , HIV Integrase/drug effects , Intercellular Signaling Peptides and Proteins/pharmacology , Peptides/pharmacology , Amino Acid Sequence , Catalysis/drug effects , DNA/chemistry , HIV Integrase/chemistry , HIV Integrase/genetics , HIV Integrase Inhibitors/chemistry , Humans , Intercellular Signaling Peptides and Proteins/chemistry , Molecular Sequence Data , Mutation , Peptides/chemistry , Protein Conformation , Protein Structure, Tertiary
15.
J Med Chem ; 51(5): 1136-44, 2008 Mar 13.
Article in English | MEDLINE | ID: mdl-18281931

ABSTRACT

Two decades of intensive research efforts have led to the discovery of a large number of HIV-1 integrase (IN) inhibitors. Recently, the United States Food and Drug Administration (US FDA) approved MK-0518, or raltegravir ( 1), as the first IN inhibitor for HIV/AIDS treatment. Growing clinical evidence also demonstrates that the emergence of HIV-1 virus strains bearing IN amino acid substitutions that confer resistance to IN inhibitors is inevitable. The discovery of second generation inhibitors with potency against viral strains bearing drug resistant IN substitutions is necessary for ongoing effective treatment of viral infections. We generated common feature pharmacophore hypotheses using a training set of quinolone 3-carboxylic acid IN inhibitors, including the clinical candidate GS-9137 ( 2). A database search of small molecules using the quinolone 3-carboxylic acid pharmacophore model, followed by in vitro evaluation of selected hits in an assay specific to IN, resulted in the discovery of potential leads with diverse structural scaffolds useful for the design of second generation IN inhibitors.


Subject(s)
HIV Integrase Inhibitors/chemistry , HIV-1/drug effects , Models, Molecular , Quinolones/chemistry , Animals , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Cell Line , Databases, Factual , Drug Design , HIV Integrase/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , Humans , Mice , Molecular Conformation , Quinolones/pharmacology , Structure-Activity Relationship
16.
Med Res Rev ; 28(1): 118-54, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17979144

ABSTRACT

HIV-1 integrase (IN) catalyzes the integration of proviral DNA into the host genome, an essential step for viral replication. Inhibition of IN catalytic activity provides an attractive strategy for antiretroviral drug design. Currently two IN inhibitors, MK-0518 and GS-9137, are in advanced stages of human clinical trials. The IN inhibitors in clinical evaluation demonstrate excellent antiretroviral efficacy alone or in combination regimens as compared to previously used clinical antiretroviral agents in naive and treatment-experienced HIV-1 infected patients. However, the emergence of viral strains resistant to clinically studied IN inhibitors and the dynamic nature of the HIV-1 genome demand a continued effort toward the discovery of novel inhibitors to keep a therapeutic advantage over the virus. Continued efforts in the field have resulted in the discovery of compounds from diverse chemical classes. In this review, we provide a comprehensive report of all IN inhibitors discovered in the years 2005 and 2006.


Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV-1/drug effects , Amino Acid Sequence , Clinical Trials as Topic , Drug Design , Humans , Molecular Sequence Data
17.
Bioorg Med Chem Lett ; 17(22): 6155-9, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17911021

ABSTRACT

The beta-diketoacid class of HIV-1 integrase (IN) inhibitors represent the first potent class of compounds specific for the strand transfer catalytic activity of the viral enzyme. Previously, utilizing a beta-diketoacid pharmacophore as a search query, we identified a substituted 2-pyrrolinone with modest IN inhibitory activity from a database of small-molecules [Dayam, R.; Sanchez, T.; Neamati, N. J. Med. Chem.2005, 48, 8009]. In efforts to optimize this class of IN inhibitors, we carried out a structure-activity relationship analysis around the 2-pyrrolinone core. Here, we present a new class of 2-pyrrolinone IN inhibitors.


Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV Integrase/drug effects , Pyrroles/chemistry , Pyrroles/pharmacology , Furans/chemistry , Furans/pharmacology , Humans , Molecular Structure , Organic Chemicals/chemistry , Organic Chemicals/pharmacology , Pyrrolidinones , Quinolones/chemistry , Quinolones/pharmacology , Raltegravir Potassium , Triazoles/chemistry , Triazoles/pharmacology
18.
Bioorg Med Chem Lett ; 17(23): 6472-5, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17950601

ABSTRACT

The previously discovered salicylhydrazide class of compounds displayed potent HIV-1 integrase (IN) inhibitory activity. The development of this class of compounds as antiretroviral agents was halted due to cytotoxicity in the nanomolar to sub-micromolar range. We identified a novel class of non-cytotoxic hydrazide IN inhibitors utilizing the minimally required salicylhydrazide substructure as a template in a small-molecule database search. The novel hydrazides displayed low micromolar IN inhibitory activity and are several hundred-fold less cytotoxic than previously disclosed salicylhydrazide IN inhibitors.


Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase/metabolism , Hydrazines/chemistry , Cell Line, Tumor , Cytotoxins/analysis , Cytotoxins/chemistry , Cytotoxins/pharmacology , Databases, Factual , HIV Integrase Inhibitors/analysis , HIV Integrase Inhibitors/pharmacology , Humans , Hydrazines/analysis , Hydrazines/pharmacology
19.
Drugs R D ; 8(3): 155-68, 2007.
Article in English | MEDLINE | ID: mdl-17472411

ABSTRACT

From the discovery of HIV-1 integrase (IN) inhibitors using enzyme-based assays in 1992, it has taken 15 years to achieve success in human clinical trials. Currently available antiretroviral drugs set high clinical standards in efficacy and long-term safety for upcoming novel HIV/AIDS therapeutic agents. The results from advanced stages of human clinical trials with IN inhibitors indicate a promising future for these compounds as a novel class of antiretroviral drugs. Success and failure of previously discovered antiretroviral drugs have taught us that there are no magic bullets in eradicating HIV. However, approval of drugs selectively targeting IN has long been awaited. There is once again a surge of interest in the field focusing on clinical development of IN inhibitors. Here, we summarise the current status of IN inhibitors under clinical development. These agents include S-1360, GSK-364735, L-870,810, L-870,812, MK-0518, GS-9137, L-900564, GS-9224, and BMS-707035. Promising antiviral activity has already been achieved with MK-0518 and GS-9137 in late-stage clinical studies.


Subject(s)
HIV Integrase Inhibitors/therapeutic use , HIV-1/drug effects , Clinical Trials as Topic , Drug Evaluation, Preclinical , Drugs, Investigational/chemistry , Drugs, Investigational/pharmacology , Drugs, Investigational/therapeutic use , HIV Infections/drug therapy , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Humans , Virus Integration/drug effects
20.
Bioorg Med Chem ; 15(14): 4985-5002, 2007 Jul 15.
Article in English | MEDLINE | ID: mdl-17502148

ABSTRACT

Recently, we reported small-molecule chalcones as a novel class of HIV-1 integrase (IN) inhibitors. The most potent compound showed an IC50 value of 2 microM for both IN-mediated 3'-processing and strand transfer reactions. To further utilize the chalcones, we developed pharmacophore models to identify chemical signatures important for biological activity. The derived models were validated with a collection of published inhibitors, and then were applied to screen a subset of our small molecule database. We tested 71 compounds in an in vitro assay specific for IN enzymatic activity. Forty-four compounds showed inhibitory potency<100 microM, and four of them exhibited IC50 values<10 microM. One compound, 62, with an IC50 value of 0.6 microM, displayed better potency than the original chalcone 2 against the strand transfer process. This study demonstrates the systematic use of pharmacophore technologies to discover novel structurally diverse inhibitors based on lead molecules that would exhibit poor characteristics in vivo. The identified compounds have the potential to exhibit favorable pharmacokinetic and pharmacodynamic profiles.


Subject(s)
Chalcone/chemistry , Chalcone/pharmacology , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Catalysis , Databases, Protein , HIV Integrase/metabolism , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Structure-Activity Relationship
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