INDOLE AMIDE DERIVATIVES: SYNTHESIS, STUCTURE-ACTIVITY RELATIONSHIPS AND MOLECULAR MODELLING STUDIES OF A NEW SERIES OF HISTAMINE H1-RECEPTOR ANTAGONISTS.

A number of indole amide derivatives bearing a basic side chain, in which the indole ring replaces the isoster benzimidazole nucleus typical of some well-known antihistamines, were prepared and tested for their H1-antihistaminic activity. The 1-benzyl-3-indolecarboxamides 32–42 showed antihistaminic (H1) activity (pA2 6–8); the 3-indolylglyoxylylamides 7–16 and the 2-indolecarboxamides 48–56 showed little or no activity. Insertion of the basic side chain of the active 3-indolecarboxamide derivatives into a piperazine ring (compounds 57–59) led to a dramatic loss of activity. All the active compounds proved to be competitive antagonists, since the values of the regression slope were not statistically different from 1. The most active compounds, 32, 33, 38–41, were also tested both in vitro for their anticholinergic activity and in vivo for their ability to antagonize histamine-induced cutaneous vascular permeability in rats. The biological results and the structure–activity relationships of the novel compounds are discussed in the light of molecular modelling studies, taking the molecule of astemizole as a model, and referring to proposed H1-receptor pharmacophore model

Pharmacological characterization of a new Ca2+ sensitizer

The benzimidazole molecule was modified to synthesize a Ca(2+) sensitizer devoid of additional effects associated with Ca(2+) overload. Newly synthesized compounds, termed 1, 2, 3, 4, and 5, were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Compound 3 resulted as the most effective positive inotropic agent, and experiments were performed to study its mechanism of action. In spontaneously beating atria, the inotropic effect of 3 was concentration-dependent (3.0 microM-0.3 mM). Compound 3 was more potent and more active than the structurally related Ca(2+) sensitizers sulmazole and caffeine, but unlike them it did not increase the heart rate. In electrically driven atria, the inotropic activity of 3 was well preserved and it was not inhibited by propranolol, prazosin, ranitidine, pyrilamine, carbachol, adenosine deaminase, or ruthenium red. At high concentrations (0.1-1.0 mM) 3 inhibited phosphodiesterase-III, whereas it did not affect Na(+)/K(+)-ATPase, sarcolemmal Ca(2+)-ATPase, Na(+)/Ca(2+) exchange carrier, or sarcoplasmic reticulum Ca(2+) pump activities of guinea pig heart. In skinned fibers obtained from guinea pig papillary muscle and skeletal soleus muscle, compound 3 (0.1 mM, 1 mM) shifted the pCa/tension relation curve to the left, with no effect on maximal tension and no signs of toxicity. Compound 3 did not influence the basal or raised tone of guinea pig isolated aorta rings, whose cells do not contain the contractile protein troponin. The present results indicate that the inotropic effect of compound 3 seems to be primarily sustained by sensitization of the contractile proteins to Ca(2+)

N,N-Dialkyl-2-phenylindol-3-ylglyoxylamides. A new class of Potent and Selective Ligands at the Peripheral Benzodiazepine Receptor.

We report the synthesis and the affinity data at both the peripheral (PBR) and the central benzodiazepine receptors of a series of N,N-dialkyl-2-phenylindol-3-ylglyoxylamide derivatives III, designed as conformationally constrained analogues of 2-phenylindole-3-acetamides II such as FGIN-1-27. Most of the new compounds showed a high specificity and affinity for PBR, with Ki in the nanomolar to subnanomolar range. The most potent ligands (4−7, 9, 13−27) stimulated steroid biosynthesis in rat C6 glioma cells with a potency similar to or higher than that of classical ligands. The SARs of this new class of compounds are discussed

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

Abstract Ligands addressed to the mitochondrial Translocator Protein (TSPO) have been suggested as cell death/life and steroidogenesis modulators. Thus, TSPO ligands have been proposed as drug candidates in several diseases; nevertheless, a correlation between their binding affinity and in vitro efficacy has not been demonstrated yet, questioning the specificity of the observed effects. Since drug-target residence time is an emerging parameter able to influence drug pharmacological features, herein, the interaction between TSPO and irDE-MPIGA, a covalent TSPO ligand, was investigated in order to explore TSPO control on death/life processes in a standardized glioblastoma cell setting. After 90 min irDE-MPIGA cell treatment, 25 nM ligand concentration saturated irreversibly all TSPO binding sites; after 24 h, TSPO de-novo synthesis occurred and about 40 % TSPO binding sites resulted covalently bound to irDE-MPIGA. During cell culture treatments, several dynamic events were observed: (a) early apoptotic markers appeared, such as mitochondrial membrane potential collapse (at 3 h) and externalization of phosphatidylserine (at 6 h); (b) cell viability was reduced (at 6 h), without cell cycle arrest. After digitonin-permeabilized cell suspension treatment, a modulation of mitochondrial permeability transition pore was evidenced. Similar effects were elicited by the reversible TSPO ligand PIGA only when applied at micromolar dose. Interestingly, after 6 h, irDE-MPIGA cell exposure restored cell survival parameters. These results highlighted the ligand-target residence time and the cellular setting are crucial parameters that should be taken into account to understand the drug binding affinity and efficacy correlation and, above all, to translate efficiently cellular drug responses from bench to bedside

Synthesis and Antihypertensive activity of some 2-aminobenzimidazole and indole derivatives.

The synthesis of some 2-aminobenzimidazole and indole amide derivatives containing a 2,6-dichloroaniline moiety is described. The preparation of a theophylline derivative is also reported. All the compounds tested showed no appreciable antihypertensive activity on spontaneously hypertensive rats

Synthesis of purinobenzothiazine and pyridothiazinopurine derivatives. Two new heterocyclic ring systems

The synthesis of derivatives of two new heterocyclic systems, purino[8,7-b][1,3]benzothiazine and pyrido[3′,2′:5,6][1,3]thiazino[3,2-f]purine, was effected by the Ullmann reaction between 8-mercaptotheophylline or 8-bromotheophylline with the appriopriately substituted benzoic or nicotinic acid, respectively. The 8,8′-dithiobistheophylline is also reported

Synthesis and anti-infiammatory properties of 2-aminobenzimidazole derivatives

Several 1-alkyl or 1-aralkyl substituted 2-aminobenzimidazole derivatives, bearing an acetic or acetohydroxamic group at 3-position, were synthesized. Some of these products were tested for their antiinflammatory and analgesic properties. These compounds exhibited an antiinfammatory activity lower than that of reference drug Indomethacin. Compound 2e showed the highest efficacy, but not in a dose-related manner. Only compounds 3a and 16 exhibited some analgesic activity, but at a very high dose

Synthesis of novel 1-aryl[1]benzoxepino[5,4-c]pyrazole and [1]benzoxepino[5,4-d]pyrimidine derivatives

Several 1-aryl[1]benzoxepinopyrazoles were prepared by reaction of 4- hydroxymethylene[1]benzoxepinones with appropriate phenylhydrazine hydrochlorides. The direct condensation of hydroxymethylenebenzoxepinones with variously substituted amidines failed to give benzoxepinopyrimidines. These compounds were obtained via the key intermediates morpholine enaminobenzoxepinones

Synthesis of some 5H,12H-[1]benzoxepino[4,3-b]indol-6-ones. A new heterocyclic ring system

The synthesis of the title compounds 5H,12H-[1]benzoxepino[4,3-b]indol-6- ones 10 was effected by the Fischer indole cyclization of some 2,3-dihydro- 4-phenylhydrazono[1]benzoxepin-5-ones 9, obtained from the 3,4-dihydro-4- hydroxymethylene[1]benzoxepin-5(2-H)-ones 7 by the Japp-Klingemann reaction. The structure of these new heterocyclic compounds was supported by ir, 1H nmr and ms spectral data