A focus on heme oxygenase-1 (HO-1) inhibitors.

The aim of this review is to highlight the advances in the field of heme oxygenase-1 (HO-1) inhibitors over the past years, particularly from a medicinal chemistry point of view; progresses made in the field strongly helped to clarify physiological roles of the heme oxygenase (HO) system. HO is a family of ubiquitously expressed enzymes which regulate the regiospecific catabolism of heme leading to the formation of equimolar amounts of carbon monoxide (CO), ferrous iron (Fe⁺⁺), and biliverdin. HO exists in two distinct, catalytically active isoforms: HO-1 and HO-2. HO-1 is an inducible 32-kDa protein, while HO-2 is a constitutively synthesized 36-kDa protein and generally is unresponsive to any of the inducers of HO-1. A third isoform, HO-3, is still an elusive protein. The HO system, along with its catabolism products, is involved in a variety of crucial physiological functions, including cytoprotection, inflammation, anti-oxidative effects, apoptosis, neuro-modulation, immune-modulation, angiogenesis, and vascular regulation. The use of selective HO inhibitors is a very important tool to clarify the role of the HO system and the mechanisms underlying its physiological effects and pathological involvement; due to the inducible nature of HO-1, selective inhibition of HO-1 isoform is generally preferable. Notably, HO-1 inhibitors may be also beneficial in therapeutic applications and have been mainly studied for treatment of hyperbilirubinemia and certain types of cancer. Historically, the first molecules used as non selective HO-1 inhibitors were metalloporphyrins (Mps). The subsequent development of the imidazole-dioxolane derivatives afforded the first generation of non-porphyrin based, isozyme selective HO-1 inhibitors.

Serotonin 5-HT3 and 5-HT4 ligands: an update of medicinal chemistry research in the last few years.

The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is one of the most studied neurotransmitters in the central nervous system. It acts through the activation of at least fourteen 5-HT receptor subtypes. Over the last two decades, high attention was devoted to the 5-HT(3) and 5-HT(4) receptors due to their colocalization in the gastrointestinal tract and because their ligands are useful in the treatment of intestinal serotonergic system dysfunctions. The focus of this review is to discuss the literature concerning recent advances on 5-HT(3)R and 5-HT(4)R ligands and their structure-activity relationships from a medicinal chemistry perspective. During the last few years, new and significant progresses have been made in the field of novel potent and selective ligands, mixed ligands, agonists, partial agonists, and antagonists, and a number of patents have been filed. Furthermore several ligands targeting the 5-HT(3)R and 5-HT(4)R have been proposed for novel therapeutic indications such as the treatment of various psychiatric disorders.

Synthesis of 1,2,4-triazole derivatives: binding properties on endothelin receptors.

In the present study we describe the synthesis of a new series of 1,2,4-triazoles: [3-(arylmethyl)thio-5-aryl-4H-[1,2,4]triazol-4-yl]acetic acids 5a-g, [5-(arylmethyl)thio-3-aryl-1H-[1,2,4]triazol-1-yl]acetic acids 8a-d, and [3-(aryl-methyl)thio-5-aryl-1H-[1,2,4]triazol-1-yl] acetic acids 9a-d. These compounds were tested in binding assays to evaluate their ability as ligands for human ET(A) and ET(B) receptors stably expressed in CHO cells; some of the tested compounds showed affinity in the micromolar range.

Imidazole derivatives as antioxidants and selective inhibitors of nNOS.

The reperfusion of ischemic tissue often delays its physiological and functional recovery; this paradoxical effect is ascribed to increased release of free radicals including O(2)(-) and NO. For these reasons, scavenging reactive oxygen species or inhibition the NO synthesis has been shown to result in an enhanced neuronal survival after cerebral ischemia. Many authors believe that therapy for stroke patients would be a cocktail of drugs with various mechanisms of action. Combination therapy is a difficult and complicated avenue for drug development because of the possibility of drug-drug interactions. An alternative approach would be to combine multiple activities within the same compound. In consideration of the free-radical scavenging and inhibitory effect on NOS of various natural and synthetic compounds, the aim of this study was to analyze the antioxidant properties of some imidazole derivatives previously synthesized in our laboratory. Results obtained in the present study provide evidence that tested compounds exhibit interesting antioxidant properties, expressed either by their capacity to scavenge free radicals or their ability to reduce lipid peroxidation. In particular, compounds A and B represent chemical structures which can be easily modified to improve the observed antioxidant properties and to provide new therapeutic strategies focused on multiple downstream events.

Novel inhibitors of neuronal nitric oxide synthase.

Selective inhibitors of neuronal nitric oxide synthase (nNOS), which are devoid of any effect on the endothelial isoform (eNOS), may be required for the treatment of some neurological disorders. In our search for novel nNOS inhibitors, we recently described some 1-[(Aryloxy)ethyl]-1H-imidazoles as interesting molecules for their selectivity for nNOS against eNOS. This work reports a new series of 1-[(Aryloxy)alkyl]-1H-imidazoles in which a longer methylene chain is present between the imidazole and the phenol part of molecule. Some of these molecules were found to be more potent nNOS inhibitors than the parent ethylenic compounds, although this increase in potency resulted in a partial loss of selectivity. The most interesting compound was investigated to establish its mechanism of action and was found to interact with the tetrahydrobiopterin (BH(4)) binding site of nNOS, without interference with any other cofactors or substrate binding sites.

Synthesis of new 3-methylthio-5-aryl-4-isothiazolecarbonitriles with broad antiviral spectrum.

The isothiazole derivative 3-methylthio-5-(4-OBn-phenyl)-4-isothiazolecarbonitrile, coded IS-50, which in previous studies had exhibited a broad antipicornavirus spectrum of action, was selected as the model for the synthesis of a new series of 3-methylthio-5-aryl-4-isothiazolecarbonitriles. These compounds were prepared in good yield (from 66 to 82%) by alkylation of 3-methylthio-5-(4-hydroxyphenyl)-4-isothiazolecarbonitrile with suitable bromides in the presence of acetone; only the 4-cyanophenoxy derivatives were obtained in a yield of less than 30%. All the compounds were screened against a panel of 17 representative human rhinovirus (HRV) serotypes belonging to both A and B groups, enteroviruses polio 1, ECHO 9 and Coxsackie B1, cardiovirus EMC, measles virus, and herpes simplex virus type 1 (HSV-1). Our results demonstrate that HRV 86 (group A) and HRVs 39 and 89 (group B) are the rhinovirus serotypes more susceptible to the action of these compounds. Isothiazole derivatives with a longer intermediate alkyl chain exhibited good activity against polio 1 and ECHO 9. The compound bearing a butyl group between the two phenoxy rings showed the lowest IC(50) against Coxsackie B1 and measles viruses. No activity against HSV-1 was detected with any of the compounds screened.

Progress in the development of selective nitric oxide synthase (NOS) inhibitors.

Nitric oxide (NO), a molecular messenger synthesized by nitric oxide synthase (NOS) from L-arginine and molecular oxygen, is involved in a number of physiological and pathological processes in mammalians. Three structurally distinct isoforms of NOS have been identified: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). Although NO mediates several physiological functions, overproduction of NO by nNOS has been reported in a number of clinical disorders including acute (stroke) and chronic (schizophrenia, Alzheimer s, Parkinson s and AIDS dementia) neurodegenerative diseases, convulsions and pain; overproduction of NO by iNOS has been implicated in various pathological processes including septic shock, tissue damage following inflammation and rheumatoid arthritis. On the contrary, NO produced by eNOS has only physiological roles such as maintaining physiological vascular tone. Accordingly, selective inhibition of nNOS or iNOS vs eNOS may provide a novel therapeutic approach to various diseases; in addition selective inhibitors may represent useful tools for investigating other biological functions of NO. For these reasons, after the identification of N-methyl-L-arginine (L-NMA) as the first inhibitor of NO biosynthesis, design of selective NOS inhibitors has received much attention. In this article the recent developments of new molecules endowed with inhibitory properties against the various isoforms of NOS are reviewed. Major focus is placed on structure-activity-selectivity relationships especially concerning compounds belonging to the non-amino acid-based inhibitors.

Inhibition of neuronal nitric oxide synthase by N-phenacyl imidazoles.

Nitric oxide (NO) mediates a series of physiological processes, including regulation of vascular tone, macrofage-mediated neurotoxicity, platelet aggregation, learning and long-term potentiation, and neuronal transmission. Although NO mediates several physiological functions, overproduction of NO can be detrimental and play multiple roles in several pathological diseases. Accordingly, more potent inhibitors, more selective for neuronal nitric oxide synthase (nNOS) than endothelial NOS (eNOS) or inducible NOS (iNOS), could be useful in the treatment of cerebral ischemia and other neurodegenerative diseases. We recently described the synthesis of a series of imidazole derivatives. Among them N-(4-nitrophenacyl) imidazole (A) and N-(4-nitrophenacyl)-2-methyl-imidazole (B) were considered selective nNOS inhibitors. In the present study the action mechanism of compounds A and B was analyzed. Spectral changes observed in the presence of compound A indicate that this inhibitor exerts its effect without interaction with heme iron. Moreover compounds A and B, inhibit nNOS "noncompetitively" versus arginine, but "competitively" versus BH(4).

Synthesis of new 3,4,5-trisubstituted isothiazoles as effective inhibitory agents of enteroviruses.

The synthesis and evaluation of 3,4,5-trisubstituted isothiazoles as antiviral agents led to the discovery of several compounds effective in vitro against enteroviruses polio 1 and ECHO 9. Structure-activity relationship studies revealed that a short thioalkyl chain in the 3-position and a methyl ester group in the 4-position are the structural components that, to a large extent, contribute to the positive biological profile in terms of both selectivity and low cytotoxicity. Under one-step growth conditions, methyl 3-methylthio-5-phenyl-4-isothiazolecarboxilate caused the greatest activity if added within 1 h after poliovirus adsorption. These data suggest interference with early events of viral replication.

Synthesis and antiviral activity of a new series of 4-isothiazolecarbonitriles.

A series of 4-isothiazolecarbonitriles was synthesized and screened for in vitro antiviral activity. The effect of various substituents on the phenyl ring, as well as the substitution of the phenyl for other aromatic and heteroaromatic rings, was examined to establish the requirements for optimum activity. The most active member of the series, 3methylthio-5-phenyl-4-isothiazolecarbonitrile, exhibited a high level of activity against enteroviruses polio 1 and ECHO 9. Preliminary studies on its mechanism of action indicated that this compound had an effect on an early event in the replication of poliovirus type 1.

Synthesis of substituted [1]benzothieno[2,3-b]pyrazines and their ability to antagonize KCl induced contractions.

A series of substituted [1]benzothieno [2,3-b]pyrazines, structurally related to caroverine, was synthesized. Some of these compounds showed an appreciable inhibition towards KCl induced contractions on isolated rat aortic rings, and a lower potency towards negative inotropic activity tested on isolated guinea pig atrium.

Synthesis and antifungal activity of pyrido[3',2':4,5]thieno[3,2-d]- 1,2,3-triazine derivatives.

The antimicrobial activity of some pyrido[3',2':4,5]thieno[3,2-d]- 1,2,3-triazine derivatives has been studied. Some compounds proved effective against microorganisms in vitro, compounds 3a and 3c in particular exhibited antifungal activity, comparable to MCZ, against hyphomycetes.

Synthesis and pharmacological properties of 3-alkylthio derivatives of isothiazolothieno-1,2,3-triazine.

Some 3-alkylthio- derivatives of 7-chloroisothiazolothieno-1,2,3-triazine and of isothiazolothieno-1,2,3-triazin-7(4H)one were prepared. The synthesized compounds were subjected to pharmacological screening for antiallergic, antiinflammatory and analgesic activity as well as to a microbiological test in order to evaluate potential antifungal activity.

Synthesis and pharmacological properties of 2-nitro-3-substituted-amino benzo[b]thiophenes and 1-substituted benzothieno[2,3-d]imidazoles.

The synthesis of 1-substituted benzothieno[2,3-d]imidazoles and their most suitable synthesis precursor 2-nitro-3-substituted-amino benzo[b]thiophenes is reported. Most of these latter compounds show analgesic and antiinflammatory activities sometimes comparable to those of phenylbutazone with less toxicity and gastric lesivity.

[Synthesis and anti-ulcer activity of 3-arylprop-2-enthionoethyl esters]. / Sintesi e attività antiulcera di 3-arilprop-2-entionoetilesteri.

A series of 3-arylprop-2-enthionoester derivatives was synthesized. These compounds were evaluated for their antiulcer activity. Derivatives [(H), (V), (VIII)] showed a noteworthy activity.

Synthesis and analgesic antiinflammatory activities of 2-aryl-ethenyl-4-aryl-thiazole-5-acetic acids.

A series of fifty-five 2-aryl-ethenyl-4-aryl-thiazole-5-acetic acids (IV-LVIII) were synthesized and evaluated for analgesic and antiinflammatory activities. Most of the synthesized compounds showed a good analgesic activity whereas some exhibited significant antiinflammatory activity.

[Synthesis and pharmacologic activity of 2-arylethenylthiazol-4-acetic and 4-carboxylic acids]. / Sintesi e attività farmacologica di acidi 2-arileteniltiazol-4-acetici e 4-carbossilici.

Two new series of 2-aryletenylthiazolo-4-acetic (IV-XII) and 4-carboxylic (XIII-XXI) acids substituted with alkoxy groups in the benzene ring were synthesized. The compounds were subjected to comparative tests of antiinflammatory, analgesic and antipyretic activity.

[Synthesis and fungistatic activity of 3-(2-dialkylaminoethylthio)thieno [2,3-c] and [3,2-d] isothiazole derivatives]. / Sintesi ed attività fungistatica di derivati 3-(2-dialchilamminoetiltio)tieno [2,3-c] e [3,2-d]isotiazolici.

A series of 5-acyl-4-amino-3-(2-dialkylaminoethyl)thieno-[2,3-c] and [3,2-d]isothiazole derivatives was synthesized. The compounds were evaluated for antifungal activity.

Synthesis and pharmacological activity of 3-substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-ones.

A series of 3-substituted pyridothienopyrimidin-4(3H)-ones has been synthesized from 2,7,9-trimethyl-4H-pyrido[3',2':4,5]thieno-[3,2-d] [ 1,3]oxazin-4-one. These compounds have been evaluated for analgesic, anti-inflammatory and antipyretic activities. The ulcerogenic effect of the compounds has been also studied.