ABSTRACT
We discovered inhibitors of the restriction enzymes EcoRI, BamHI and HindIII by screening our library of compounds with a phenethylphenylphthalimide skeleton, based on α-glucosidase inhibitors and liver X receptor antagonists derived from thalidomide. Structural development afforded the potent restriction enzyme inhibitors 25 and 26.
Subject(s)
Deoxyribonuclease BamHI/antagonists & inhibitors , Deoxyribonuclease EcoRI/antagonists & inhibitors , Deoxyribonuclease HindIII/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Isoindoles/chemistry , Phthalimides/chemistry , Thalidomide/chemistry , Deoxyribonuclease BamHI/metabolism , Deoxyribonuclease EcoRI/metabolism , Deoxyribonuclease HindIII/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors , Isoindoles/chemical synthesis , Isoindoles/pharmacology , Liver X Receptors , Orphan Nuclear Receptors/antagonists & inhibitors , Orphan Nuclear Receptors/metabolism , Phthalimides/chemical synthesis , Phthalimides/pharmacology , alpha-Glucosidases/metabolismABSTRACT
Introduction of an alkylcarboxylic acid unit, which is a partial structure of endogenous peroxisome proliferator-activated receptor (PPAR) ligands, into a phenethylphenylphthalimide skeleton, which possesses liver X receptor (LXR) antagonistic activity, afforded novel PPAR ligands. The results of structure-activity relationship analysis and docking studies led us to the potent PPAR agonists 13c-e. The absolute configuration of 13c-e affects the PPAR subtype selectivity.
Subject(s)
Orphan Nuclear Receptors/antagonists & inhibitors , Peroxisome Proliferator-Activated Receptors/agonists , Peroxisome Proliferator-Activated Receptors/metabolism , Phthalimides/chemistry , Phthalimides/pharmacology , Thalidomide/chemistry , Cell Line , Drug Design , Humans , Ligands , Liver X Receptors , Models, Molecular , Peroxisome Proliferator-Activated Receptors/chemistry , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity RelationshipABSTRACT
Novel dipeptidyl peptidase IV (DPP-IV) inhibitors with a phenethylphenylphthalimide skeleton were prepared based on α-glucosidase inhibitors and liver X receptor (LXR) antagonists derived from thalidomide. Representative compounds showed non-competitive inhibition of DPP-IV and 28a exhibited 10-fold selectivity for DPP-IV over DPP-8. Compound 28a is the first non-competitive, selective DPP-IV inhibitor.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Enzyme Activation/drug effects , Orphan Nuclear Receptors/antagonists & inhibitors , Phthalimides/chemistry , Thalidomide/chemistry , alpha-Glucosidases , Binding, Competitive , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Glycoside Hydrolase Inhibitors , Inhibitory Concentration 50 , Kinetics , Liver X Receptors , Molecular StructureABSTRACT
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve physical and mental pain, and to improve patients' quality of life. However, stomach irritation is a major side effect. Most NSAIDs inhibit cyclooxygenases (COXs), and inhibition of COX-1 on the stomach mucous membrane is thought to be responsible for the gastric disturb- ance. Consequently, development efforts have focused on COX-2-selective inhibitors, while COX-1-selective inhibitors have been rather neglected. Subsequently, however, it was shown that inhibition of either COX-1 or COX-2 alone does not induce gastric damage. Therefore, we have developed the COX-1-selective inhibitor N-(4-aminophenyl)-4-trifluoromethylbenzamide (TFAP), which shows analgesic activity without causing gastric damage. However, metabolism of TFAP generates a colored metabolite, resulting in red-purple coloration of urine after administration. In addition, the analgesic activity of TFAP is weaker than that of indomethacin. Thus, we designed a series of new COX-1-selective inhibitors, the 5-amino-2-ethoxy-N-(substituted)benzamide (ABEX) series, in order to avoid formation of the colored metabolite by modifying the diaminopyridine skeleton. As a result of structural modification and in vitro and in vivo testing of compounds in the ABEX series, we found a novel COX-1-selective inhibitor, 5-amino-2-ethoxy-N-(3-trifluoromethylphenyl)benzamide (ABEX-3TF), which shows better analgesic activity than indomethacin, and does not cause coloration of urine.
Subject(s)
Aminopyridines , Benzamides , Cyclooxygenase 1 , Cyclooxygenase Inhibitors , Drug Design , Aminopyridines/adverse effects , Aminopyridines/metabolism , Aminopyridines/pharmacology , Analgesics , Benzamides/adverse effects , Benzamides/metabolism , Benzamides/pharmacology , Cyclooxygenase Inhibitors/adverse effects , Cyclooxygenase Inhibitors/metabolism , Cyclooxygenase Inhibitors/pharmacology , Gastric Mucosa/drug effects , HumansABSTRACT
We previously found that N-(4-aminophenyl)-4-trifluoromethylbenzamide (TFAP), a COX-1 inhibitor, exhibits an analgesic effect without causing gastric damage. Unfortunately, TFAP causes reddish purple coloration of urine, and its analgesic effect is less potent than that of indomethacin. Herein we describe our study focusing on the development of 4- and 5-amino-2-alkoxy-N-phenylbenzamide scaffolds, designed on the basis of the structures of TFAP and parsalmide, another known COX-1 inhibitory analgesic agent. 5-Amino-2-ethoxy-N-(2- or 3-substituted phenyl)benzamide derivatives exhibited analgesic activity in a murine acetic acid induced writhing test. Among these compounds, 5-amino-2-ethoxy-N-(2-methoxyphenyl)benzamide (9 v) possesses potent COX-1 inhibitory and analgesic activities, similar to those of indomethacin. In addition, 5-amino-2-ethoxy-N-(3-trifluoromethylphenyl)benzamide (9 g) showed a more potent analgesic effect than indomethacin or 9 v without causing apparent gastric damage or coloration of urine, although its COX-1 inhibitory activity was weaker than that of indomethacin or 9 v. Thus, 9 g and 9 v appear to be promising candidates for analgesic agents and are attractive lead compounds for further development of COX-1 inhibitors.
Subject(s)
Analgesics/chemical synthesis , Benzamides/chemistry , Cyclooxygenase 1/chemistry , Cyclooxygenase Inhibitors/chemical synthesis , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Benzamides/chemical synthesis , Benzamides/therapeutic use , Binding Sites , Computer Simulation , Cyclooxygenase 1/metabolism , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/therapeutic use , Drug Design , Edema/chemically induced , Edema/drug therapy , Male , MiceABSTRACT
Swine-origin influenza A virus has caused pandemics throughout the world and influenza A is regarded as a serious global health issue. Hence, novel drugs that will target these viruses are very desirable. Influenza A expresses an RNA polymerase essential for its transcription and replication which comprises PA, PB1, and PB2 subunits. We identified potential novel anti-influenza agents from a screen of 34 synthesized phenethylphenylphthalimide analogs derived from thalidomide (PPT analogs). For this screen we used a PA endonuclease inhibition assay, a PB2 pathogenicity-determinant domain-binding assay, and an anti-influenza A virus assay. Three PPT analogs, PPT-65, PPT-66, and PPT-67, were found to both inhibit PA endonuclease activity and retard the growth of influenza A, suggesting a correlation between their activities. PPT-28 was also found to inhibit the growth of influenza A. These four analogs have a 3,4-dihydroxyphenethyl group in common. We also discuss the possibility that 3,4-dihydroxyphenethyl group flexibility may play an important functional role in PA endonuclease inhibition. Another analog harboring a dimethoxyphenethyl group, PPT-62, showed PB2 pathogenicity-determinant domain-binding activity, but did not inhibit the growth of the virus. Our present results indicate the utility of the PA endonuclease assay in the screening of anti-influenza drugs and are therefore useful for future strategies to develop novel anti-influenza A drugs and for mapping the function of the influenza A RNA polymerase subunits.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Influenza A virus/drug effects , Influenza, Human/drug therapy , Thalidomide/chemistry , Thalidomide/pharmacology , Animals , Antiviral Agents/chemical synthesis , Cell Line , DNA-Directed RNA Polymerases/metabolism , Dogs , Humans , Influenza A virus/enzymology , Orthomyxoviridae Infections/drug therapy , Phthalimides/chemical synthesis , Phthalimides/chemistry , Phthalimides/pharmacology , Stilbenes/chemical synthesis , Stilbenes/chemistry , Stilbenes/pharmacology , Thalidomide/chemical synthesisABSTRACT
Novel glycogen phosphorylase a (GPa) inhibitors with a phenethylphenylphthalimide skeleton were prepared based on alpha-glucosidase inhibitors and liver X receptor (LXR) antagonists derived from thalidomide. Their structure-activity relationships were analyzed. Some of the compounds thus prepared showed potent inhibitory activity against rabbit muscle GPa with more than 10-fold greater efficacy than a typical GPa inhibitor, 1,4-dideoxy-1,4-imino-D-arabinitol.
Subject(s)
Enzyme Inhibitors/chemistry , Glycogen Phosphorylase, Liver Form/antagonists & inhibitors , Glycogen Phosphorylase, Muscle Form/antagonists & inhibitors , Glycoside Hydrolase Inhibitors , Orphan Nuclear Receptors/antagonists & inhibitors , Phthalimides/chemical synthesis , Thalidomide/analogs & derivatives , Thalidomide/pharmacology , Animals , Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase, Liver Form/chemistry , Glycogen Phosphorylase, Muscle Form/chemistry , Liver X Receptors , Orphan Nuclear Receptors/chemistry , Phthalimides/pharmacology , Rabbits , Thalidomide/chemistryABSTRACT
Liver X receptor (LXR) alpha/beta dual agonists are candidate medicaments for the treatment of metabolic syndrome, because their biological actions include increasing cholesterol efflux mediated by LXRbeta. However, their clinical application is currently limited by their enhancing effect on triglyceride (TG) synthesis mediated by LXRalpha. Combination of an LXRalpha-selective antagonist with an LXRalpha/beta dual agonist may overcome this disadvantage. In the present work, structural development studies of phenethylphenyl phthalimide 9, which possesses LXRalpha/beta dual-antagonistic activity and alpha-glucosidase-inhibitory activity, led to the LXRalpha-selective antagonist 23f. Specific alpha-glucosidase inhibitors were also obtained.
Subject(s)
DNA-Binding Proteins/antagonists & inhibitors , Glycoside Hydrolase Inhibitors , Phthalimides/chemistry , Phthalimides/pharmacology , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Saccharomyces/enzymology , Cell Line , DNA-Binding Proteins/metabolism , Humans , Kidney/cytology , Liver X Receptors , Molecular Structure , Orphan Nuclear Receptors , Phthalimides/chemical synthesis , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity Relationship , Thalidomide/analogs & derivatives , Thalidomide/chemical synthesis , Thalidomide/pharmacology , alpha-Glucosidases/metabolismABSTRACT
Malaria is a leading cause of death in developing countries, and the emergence of strains resistant to the main therapeutic agent, chloroquine, has become a serious problem. We have developed cationic-dimer type antimalarials, MAP-610 and PMAP-H10, which are structurally different from chloroquine. In this study, we introduced several substituents on the terminal phenyl rings of PMAP-H10. The electronic and hydrophobic properties of the substituents were correlated with the antimalarial activity and cytotoxicity of the compounds, respectively. Studies with synchronized cultures of malarial plasmodia showed that our cationic-dimers act selectively between the schizont stage and the ring stage of the parasitic cycle, unlike chloroquine, which has a stage-independent action. Thus, the mechanism of action of our antimalarials appears to be different from that of chloroquine, and our compounds may be effective against chloroquine-resistant strains.
Subject(s)
Antimalarials/chemistry , Antimalarials/toxicity , Chloroquine/toxicity , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Pyridinium Compounds/chemistry , Pyridinium Compounds/toxicity , Animals , Cations , Cell Line, Tumor , Chloroquine/chemistry , Dimerization , Drug Resistance , Erythrocytes/drug effects , Erythrocytes/parasitology , Humans , Inhibitory Concentration 50 , Mice , Parasitemia/drug therapy , Parasitemia/parasitology , Structure-Activity RelationshipABSTRACT
Vancomycin is mainly used as an antibacterial agent of last resort, but recently vancomycin-resistant bacterial strains have been emerging. Although new antimicrobials have been developed in order to overcome drug-resistant bacteria, many are structurally complex beta-lactams or quinolones. In this study, we aimed to create new anti-drug-resistance antibacterials which can be synthesized in a few steps from inexpensive starting materials. Since sulfa drugs function as p-aminobenzoic acid mimics and inhibit dihydropteroate synthase (DHPS) in the folate pathway, we hypothesized that sulfa derivatives would act as folate metabolite-mimics and inhibit bacterial folate metabolism. Screening of our sulfonanilide libraries, including benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors, led us to discover benzenesulfonanilides with potent anti-methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant Enterococcus (VRE) activity, that is, N-3,5-bis(trifluoromethyl)phenyl-3,5-dichlorobenzenesulfonanilide (16b) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)], and 3,5-bis(trifluoromethyl)-N-(3,5-dichlorophenyl)benzenesulfonanilide (16c) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)]. These compounds are more active than vancomycin [MIC=2.0microg/mL (MRSA), 125microg/mL (VRE)], but do not possess an amino group, which is essential for DHPS inhibition by sulfa drugs. These results suggested that the mechanism of antibacterial action of compounds 16b and 16c is different from that of sulfa drugs. We also confirmed the activity of these compounds against clinical isolates of Gram-positive bacteria.
Subject(s)
Anilides/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Enterococcus faecium/drug effects , Methicillin Resistance , Staphylococcus aureus/drug effects , Sulfonamides/chemical synthesis , Vancomycin Resistance , Anilides/pharmacology , Anilides/toxicity , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Cyclooxygenase 1/metabolism , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Cyclooxygenase Inhibitors/toxicity , Drug Design , Enterococcus faecium/isolation & purification , Humans , Male , Membrane Proteins/metabolism , Mice , Microbial Sensitivity Tests , Staphylococcus aureus/isolation & purification , Sulfonamides/pharmacology , Sulfonamides/toxicityABSTRACT
Malaria is one of the three major serious infectious diseases in the world. As the area affected by malaria includes a large proportion of developing countries, there is a need for new antimalarials that can be synthesized and supplied inexpensively. To generate low-cost antimalarials, the MAP series 6-10, bis-cation dimers, synthesized by amidating the carboxyl group of isonicotinic acid (11) with various amines and by cationizing the nitrogen atoms of the pyridine ring with the corresponding alkyl bromides, were designed. This design enabled expansion of the structural variations of bis-cation-type antimalarial compounds. The compounds bearing alkyl or phenyl groups in the amide moieties showed remarkable antimalarial activities in vitro. Moreover, 1,1'-(1,12-dodecanediyl)bis[4-[(buthylamino)carbonyl]pyridinium bromide], MAP-412 (6 d), exhibited a potent antimalarial activity (ED(50)=8.2 mg kg(-1)). Being prepared at low cost, our bis-cation-type antimalarial compounds may be useful as lead compounds for inexpensive antimalarials.