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1.
Nat Rev Drug Discov ; 14(11): 751-8, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26435527

ABSTRACT

Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.


Subject(s)
Developing Countries , Drug Discovery/trends , Foundations/trends , Malaria/drug therapy , Neglected Diseases/drug therapy , Tuberculosis/drug therapy , Animals , Communicable Diseases/drug therapy , Communicable Diseases/economics , Communicable Diseases/epidemiology , Developing Countries/economics , Drug Discovery/economics , Drugs, Generic/economics , Drugs, Generic/therapeutic use , Foundations/economics , Humans , Malaria/economics , Malaria/epidemiology , Neglected Diseases/economics , Neglected Diseases/epidemiology , Tuberculosis/economics , Tuberculosis/epidemiology
2.
Antimicrob Agents Chemother ; 56(5): 2414-9, 2012 May.
Article in English | MEDLINE | ID: mdl-22314528

ABSTRACT

Malaria continues to have a significant impact on the health of the developing world. Efforts to combat this disease now focus on combination therapy in order to stem the emergence of resistant parasites. Continued efforts are needed to discover and develop new agents for use in combination antimalarial regimens. MK-4815 is a small molecule with antimalarial activity that was identified from a large pharmaceutical compound collection using a semiautomated version of a well-established in vitro assay for the erythrocytic stages of Plasmodium falciparum. In vitro studies indicate that the compound selectively accumulates in infected red blood cells and is most effective against the metabolically active late trophozoite/early schizont stages. A variety of drug-resistant field isolates of P. falciparum were found to be as sensitive to MK-4815 as the wild-type lines. MK-4815 is orally active in a P. berghei mouse model of acute malaria. In this model, where untreated animals succumb to infection 10 to 12 days postinfection, MK-4815 was completely curative when given as a single dose of 50 mg/kg, 2 doses of 25 mg/kg, or 4.5 doses of 12.5 mg/kg. In pharmacokinetic studies with mice and rhesus monkeys, MK-4815 demonstrated oral bioavailability and low clearance. In addition, MK-4815 is inexpensive to synthesize, an important characteristic for providing affordable antimalaria therapy to the developing world. The attractive biological and pharmaceutical profile of MK-4815 demonstrates its potential for use in combination with other agents in the fight against malaria.


Subject(s)
Antimalarials/pharmacology , Malaria/drug therapy , Methylamines/pharmacokinetics , Phenols/pharmacokinetics , Plasmodium falciparum/drug effects , Administration, Oral , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacokinetics , Antimalarials/therapeutic use , Biological Availability , Drug Administration Schedule , Drug Combinations , Female , Humans , Inhibitory Concentration 50 , Macaca mulatta , Malaria/mortality , Malaria/parasitology , Methylamines/chemical synthesis , Methylamines/chemistry , Mice , Mice, Inbred BALB C , Phenols/chemical synthesis , Phenols/chemistry , Plasmodium berghei/drug effects , Plasmodium berghei/physiology , Plasmodium falciparum/physiology , Survival Rate , Trophozoites/drug effects , Trophozoites/physiology
3.
J Med Chem ; 52(11): 3505-15, 2009 Jun 11.
Article in English | MEDLINE | ID: mdl-19445514

ABSTRACT

Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.


Subject(s)
Insect Control , Insecticides , Siphonaptera , Ticks , Adipose Tissue/metabolism , Administration, Oral , Animals , Cats , Dogs , Female , Indole Alkaloids/chemical synthesis , Indole Alkaloids/pharmacokinetics , Indole Alkaloids/pharmacology , Indoles , Insecticides/administration & dosage , Insecticides/chemical synthesis , Male , Mice , Tissue Distribution
4.
Bioorg Med Chem Lett ; 19(5): 1517-21, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-19195883

ABSTRACT

Novel 2,3-diarylindoles bearing an amine substituent at the indole 5- and 6-positions have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 27.


Subject(s)
Coccidiostats/chemical synthesis , Indoles/chemical synthesis , Animals , Coccidiosis/drug therapy , Coccidiosis/enzymology , Coccidiosis/parasitology , Coccidiostats/pharmacology , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria tenella/drug effects , Eimeria tenella/enzymology , Eimeria tenella/growth & development , Indoles/pharmacology , Poultry/parasitology , Pyridines/chemical synthesis
5.
Curr Mol Med ; 8(8): 774-83, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19075675

ABSTRACT

Various types of cancers are generated through mutations or dysregulations of oncogenes/tumor suppressor genes involved in cell cycles and signaling transduction pathways. To identify cancer therapeutic targets whose inhibition selectively kills cancer cells, synthetic lethal screening is being developed to identify genes whose intervention suppresses tumor progression only when combined with the dysregulation of the genes. The recent emergence of genomic technologies, including microarray, RNA interference and chemogenomics, provides platforms to realize this concept. This review introduces the research that could successfully identify synthetic lethal genes in cancer cells harboring major gene alterations such as p53, RB, K-Ras, or Myc. We also illustrate remarkable candidate targets that were identified by synthetic lethal screening to find chemosensitizers for paclitaxel and cisplatin. Next, we introduce the chemogenomics approaches that explore chemical compounds that exhibit synthetic lethality to cancer gene alterations. Although the synthetic lethal compounds are of great interest in terms of cancer drug development, a method of identifying target proteins for the phenotypic compounds has been elusive. Finally, we demonstrate several noteworthy techniques to identify target proteins for the compounds: a Connectivity Map that compares expression profiles of compound-treated cells by pattern-matching algorithms; an siRNA/compound co-treatment assay to find enhancer genes for the phenotypes of compounds; and a state-of-the-art proteomics approach that modifies classical compound-immobilized affinity chromatography. The integration of genomic and pharmacological analyses would significantly accelerate the identification of cancer-specific synthetic lethal targets.


Subject(s)
Genes, Lethal , Genes, Synthetic , Neoplasms/genetics , Neoplasms/therapy , Gene Expression Profiling , Gene Silencing , Gene Targeting , Genetic Therapy/methods , Humans , Models, Genetic , Mutation , Neoplasms/drug therapy , Oligonucleotide Array Sequence Analysis , Oncogenes , Proteomics
8.
Eur J Med Chem ; 43(6): 1123-51, 2008 Jun.
Article in English | MEDLINE | ID: mdl-17981367

ABSTRACT

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.


Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria/drug effects , Magnetic Resonance Spectroscopy , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Spectrometry, Mass, Electrospray Ionization
9.
Bioorg Med Chem Lett ; 17(13): 3558-61, 2007 Jul 01.
Article in English | MEDLINE | ID: mdl-17475489

ABSTRACT

Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed.


Subject(s)
Coccidiosis/drug therapy , Coccidiostats/pharmacology , Imidazoles/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Animals , Chemistry, Pharmaceutical/methods , Coccidiostats/chemistry , Cyclic GMP-Dependent Protein Kinases/metabolism , Drug Design , Eimeria tenella , Models, Chemical , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship
10.
Eur J Med Chem ; 42(11-12): 1334-57, 2007.
Article in English | MEDLINE | ID: mdl-17433505

ABSTRACT

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.


Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Eimeria/drug effects , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Biological Availability , Coccidiostats/chemistry , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic GMP-Dependent Protein Kinases/metabolism , Eimeria/physiology , Imidazoles/chemistry , Inhibitory Concentration 50 , Pyridines/chemistry
12.
Nature ; 441(7091): 358-61, 2006 May 18.
Article in English | MEDLINE | ID: mdl-16710421

ABSTRACT

Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.


Subject(s)
Aminoglycosides/pharmacology , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/antagonists & inhibitors , 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/chemistry , 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/metabolism , Acetamides/pharmacology , Acetamides/toxicity , Adamantane , Aminobenzoates , Aminoglycosides/chemistry , Aminoglycosides/metabolism , Aminoglycosides/toxicity , Anilides , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/toxicity , Apoproteins/chemistry , Apoproteins/metabolism , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Crystallography, X-Ray , Linezolid , Lipids/biosynthesis , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Oxazolidinones/pharmacology , Oxazolidinones/toxicity , Streptomyces/metabolism , Substrate Specificity
14.
Bioorg Med Chem Lett ; 16(10): 2817-21, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16517161

ABSTRACT

2-(4-Fluorophenyl)-3-(4-pyridinyl)-5-substituted pyrroles were prepared and evaluated as anticoccidial agents in both in vitro and in vivo assays. Among the compounds evaluated, the dimethylamine-substituted pyrrole 19a is the most potent inhibitor of Eimeria tenella PKG (cGMP-dependent protein kinase). Further SAR studies on the side chain of the 2-pyrrolidine nitrogen did not enhance in vivo anticoccidial activity.


Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Animals , Coccidiostats/chemistry , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria tenella/drug effects , Eimeria tenella/enzymology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrroles/chemistry , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 16(9): 2479-83, 2006 May 01.
Article in English | MEDLINE | ID: mdl-16464591

ABSTRACT

Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.


Subject(s)
Antiprotozoal Agents/chemical synthesis , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria tenella/drug effects , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Animal Feed , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Chickens , Coccidiosis/drug therapy , Eimeria tenella/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Molecular Structure , Mutagenicity Tests , Oocysts/drug effects , Parasitic Sensitivity Tests , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship
16.
Antimicrob Agents Chemother ; 50(2): 519-26, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16436705

ABSTRACT

Condensing enzymes are essential in type II fatty acid synthesis and are promising targets for antibacterial drug discovery. Recently, a new approach using a xylose-inducible plasmid to express antisense RNA in Staphylococcus aureus has been described; however, the actual mechanism was not delineated. In this paper, the mechanism of decreased target protein production by expression of antisense RNA was investigated using Northern blotting. This revealed that the antisense RNA acts posttranscriptionally by targeting mRNA, leading to 5' mRNA degradation. Using this technology, a two-plate assay was developed in order to identify FabF/FabH target-specific cell-permeable inhibitors by screening of natural product extracts. Over 250,000 natural product fermentation broths were screened and then confirmed in biochemical assays, yielding a hit rate of 0.1%. All known natural product FabH and FabF inhibitors, including cerulenin, thiolactomycin, thiotetromycin, and Tü3010, were discovered using this whole-cell mechanism-based screening approach. Phomallenic acids, which are new inhibitors of FabF, were also discovered. These new inhibitors exhibited target selectivity in the gel elongation assay and in the whole-cell-based two-plate assay. Phomallenic acid C showed good antibacterial activity, about 20-fold better than that of thiolactomycin and cerulenin, against S. aureus. It exhibited a spectrum of antibacterial activity against clinically important pathogens including methicillin-resistant Staphylococcus aureus, Bacillus subtilis, and Haemophilus influenzae.


Subject(s)
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Bacteria/enzymology , Biological Products/chemistry , Enzyme Inhibitors/pharmacology , Anti-Bacterial Agents/isolation & purification , Drug Design , Fatty Acids/biosynthesis , Microbial Sensitivity Tests , RNA, Antisense/pharmacology , RNA, Messenger/chemistry , Structure-Activity Relationship
17.
Bioorg Med Chem Lett ; 16(4): 964-8, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16338135

ABSTRACT

A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies.


Subject(s)
Bacterial Toxins/antagonists & inhibitors , Pyrans/pharmacology , Animals , Anthrax/drug therapy , Anthrax/prevention & control , Antigens, Bacterial , Biological Availability , Dogs , Drug Evaluation, Preclinical , Macaca mulatta , Metalloproteases/antagonists & inhibitors , Mice , Molecular Structure , Pyrans/administration & dosage , Pyrans/chemical synthesis , Rabbits , Stereoisomerism , Structure-Activity Relationship
18.
Bioorg Med Chem Lett ; 15(20): 4570-3, 2005 Oct 15.
Article in English | MEDLINE | ID: mdl-16087336

ABSTRACT

Diaryl-(4-piperidinyl)-pyrrole derivatives bearing hydroxylated N-alkyl substituents have been synthesized and evaluated as anticoccidial agents. High potency in Et-PKG inhibition and broad-spectrum anticoccidial activities have been observed on compounds, such as 4b and 5h, which are fully efficacious in vivo at 50 ppm in feed.


Subject(s)
Coccidiostats/chemistry , Coccidiostats/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Hydroxylation , Structure-Activity Relationship
19.
Bioorg Med Chem Lett ; 15(13): 3296-301, 2005 Jul 01.
Article in English | MEDLINE | ID: mdl-15922595

ABSTRACT

Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.


Subject(s)
Coccidiostats/chemical synthesis , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Protozoan Proteins/antagonists & inhibitors , Pyrroles/chemical synthesis , Animals , Biological Availability , Chickens , Coccidiosis/drug therapy , Coccidiostats/pharmacokinetics , Coccidiostats/pharmacology , Eimeria , Half-Life , Inhibitory Concentration 50 , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Structure-Activity Relationship
20.
J Biol Chem ; 280(2): 1669-77, 2005 Jan 14.
Article in English | MEDLINE | ID: mdl-15516341

ABSTRACT

Type II fatty acid synthesis (FASII) is essential to bacterial cell viability and is a promising target for the development of novel antibiotics. In the past decade, a few inhibitors have been identified for this pathway, but none of them lend themselves to drug development. To find better inhibitors that are potential drug candidates, we developed a high throughput assay that identifies inhibitors simultaneously against multiple targets within the FASII pathway of most bacterial pathogens. We demonstrated that the inverse t(1/2) value of the FASII enzyme-catalyzed reaction gives a measure of FASII activity. The Km values of octanoyl-CoA and lauroyl-CoA were determined to be 1.1 +/- 0.3 and 10 +/- 2.7 microM in Staphylococcus aureus and Bacillus subtilis, respectively. The effects of free metals and reducing agents on enzyme activity showed an inhibition hierarchy of Zn2+ > Ca2+ > Mn2+ > Mg2+; no inhibition was found with beta-mercaptoethanol or dithiothreitol. We used this assay to screen the natural product libraries and isolated an inhibitor, bischloroanthrabenzoxocinone (BABX) with a new structure. BABX showed IC50 values of 11.4 and 35.3 microg/ml in the S. aureus and Escherichia coli FASII assays, respectively, and good antibacterial activities against S. aureus and permeable E. coli strains with minimum inhibitory concentrations ranging from 0.2 to 0.4 microg/ml. Furthermore, the effectiveness, selectivity, and the in vitro and in vivo correlations of BABX as well as other fatty acid inhibitors were elucidated, which will aid in future drug discovery.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacteria/metabolism , Fatty Acids/biosynthesis , Bacteria/enzymology , Cations, Divalent/pharmacology , Dithiothreitol/pharmacology , Drug Evaluation, Preclinical , Heterocyclic Compounds, 4 or More Rings/pharmacology , Inhibitory Concentration 50 , Kinetics , Mercaptoethanol/pharmacology , Microbial Sensitivity Tests , Sensitivity and Specificity , Substrate Specificity
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