ABSTRACT
The 2-arylvinyl moiety in 1-(3-chlorophenyl)-3-(4-piperidyl)-5-[(E)-2-(5-chloro-1H-indol-3-yl)vinyl]pyrazole 2, which has previously shown improved DNA gyrase inhibition and target-related antibacterial activity, was transformed to other groups and the in vitro antibacterial activity of the synthesized compounds was evaluated. Many of the 5-[(E)-2-arylvinyl]pyrazoles synthesized in this study exhibited potent antibacterial activity against quinolone-resistant clinical isolates of gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Pyrazoles/chemical synthesis , Topoisomerase II Inhibitors , Anti-Bacterial Agents/pharmacology , Drug Resistance , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Pyrazoles/pharmacology , Quinolones , Structure-Activity RelationshipABSTRACT
We have previously reported that (4R,5R)-5-ethyl-2-imino-4-methylthiazolidine (3) strongly inhibits inducible nitric oxide synthase (iNOS). In a successive search for strong and selective iNOS inhibitors, we, herein, describe the synthesis of the selenium analogue of 3 (4: ES-2133) and its related optically active compounds and examine their in vitro and in vivo inhibitory activity against iNOS. In addition, an alternative synthetic method to the selected compound 4 and its pharmacokinetic profile is also reported.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Nitric Oxide Synthase/antagonists & inhibitors , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/pharmacokinetics , Arginine/antagonists & inhibitors , Biological Availability , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Kinetics , Molecular Conformation , Nitric Oxide Synthase Type II , Organoselenium Compounds/chemistry , Selenium/chemistry , Structure-Activity RelationshipABSTRACT
The 4-piperidyl moiety and the pyrazole ring in 1-(3-chlorophenyl)-5-(4-phenoxyphenyl)-3-(4-piperidyl)pyrazole 2, which has previously shown improved DNA gyrase inhibition and target-related antibacterial activity, were transformed to other groups and the in vitro antibacterial activity of the synthesized compounds was evaluated. The selected pyrazole, oxazole and imidazole derivatives showed moderate inhibition against DNA gyrase and topoisomerase IV with similar IC(50) values (IC(50)=9.4-25 microg/mL). In addition, many of the pyrazole, oxazole and imidazole derivatives synthesized in this study exhibited potent antibacterial activity against quinolone-resistant clinical isolates and coumarin-resistant laboratory isolates of Gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Azoles/chemical synthesis , Topoisomerase II Inhibitors , Anti-Bacterial Agents/pharmacology , Azoles/pharmacology , DNA Gyrase/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Microbial Sensitivity Tests/statistics & numerical data , Staphylococcus aureus/drug effects , Staphylococcus aureus/enzymologyABSTRACT
In the course of our search for selective iNOS inhibitors, we have previously reported that 2-imino-1,3-oxazolidine derivatives (1) and 2-aminothiazole derivatives (2) are selective iNOS inhibitors. In order to find more potent iNOS inhibitors, we focused our efforts on the synthesis and evaluation of the inhibitory activity against iNOS and selectivity for iNOS both in vitro and in vivo of a series of 2-imino-1,3-thiazolidine derivatives (3), which are analogues of 1 and 2. Our results show that among the compounds synthesized (4R,5R)-5-ethyl-2-imino-4-methyl-1,3-thiazolidine [(4R,5R)-14a: ES-1537] exhibited potent inhibitory activity and selectivity for iNOS. In addition, ES-1537 had good pharmacokinetic profile in rats with BA value of 80%. It is therefore expected that ES-1537 may be therapeutically useful for the treatment of diseases related to excess production of NO.
Subject(s)
Enzyme Inhibitors/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Thiazoles/pharmacology , Animals , Cell Line , Enzyme Inhibitors/chemical synthesis , Female , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Nitric Oxide Synthase/blood , Nitric Oxide Synthase/drug effects , Nitric Oxide Synthase Type II , Rats , Rats, Wistar , Thiazoles/chemical synthesis , Thiazoles/pharmacokineticsABSTRACT
We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Indoles/chemical synthesis , Pyrazoles/chemical synthesis , Topoisomerase II Inhibitors , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA Topoisomerase IV/antagonists & inhibitors , Drug Resistance, Bacterial , Enterococcus faecalis/drug effects , Indoles/chemistry , Indoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Structure-Activity RelationshipABSTRACT
Nitric oxide synthase (NOS) has been divided into two major sub-enzymes, i.e. inducible NOS (iNOS) and constitutive NOS (cNOS). Although nitric oxide (NO) plays an important role as host defense mediator, excessive production of NO by iNOS has been involved in the pathology of many inflammatory diseases. Recently, we reported that the 2-imino-1,3-oxazolidine (1a) weakly inhibits iNOS and that introduction of an alkyl moiety on the oxazolidine ring of 1a enhances the inhibitory activity and selectivity for iNOS. In our search for better iNOS inhibitors, we focused our efforts on the 2-aminothiazole scaffold 3 as it possesses a ring similar to that of 1a. In this study, we evaluated the inhibitory activity of a series of 2-aminothiazole derivatives against both iNOS and neuronal NOS (nNOS). Our results show that introduction of appropriately-sized substituents at the 4- and 5-position of the 2-aminothiazole ring improves the inhibitory activity and selectivity for iNOS. We also found that the selectivity of 5a [5-(1-methyl)ethyl-4-methylthiazol-2-ylamine] and 5b [5-(1,1-dimethyl)ethyl-4-methylthiazol-2-ylamine] for iNOS was similar to that of oxazolidine derivative 1b (4-methyl-5-propyl-2-imino-1,3-oxazolidine) and much higher than that of L-NAME. However, we could not enhance the inhibitory activity against iNOS by introducing an alkyl substituent into the 2-aminothiazole ring as we could in the case of oxazolidine one. On the other hand, introduction of bulky or hydrophilic substituent at any position of the 2-aminothiazole ring remarkably decreased or even abolished the inhibitory activity against NOS.
Subject(s)
Enzyme Inhibitors/chemistry , Nitric Oxide Synthase/antagonists & inhibitors , Thiazoles/chemistry , Animals , Cell Line , Enzyme Inhibitors/pharmacology , Male , Mice , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Rats , Rats, Wistar , Structure-Activity Relationship , Thiazoles/pharmacologyABSTRACT
In our search for a novel class of inducible nitric oxide synthase (iNOS) inhibitors, 1,3-oxazolidin-2-imine was found to weakly inhibit iNOS. Further modifications of this compound resulted in a remarkable increase in both the in vivo and in vitro inhibitory activity and selectivity for iNOS.