Synthesis and antimalarial activity of new atovaquone derivatives.

In this paper we describe the design and synthesis of 18 derivatives of the antimicrobial atovaquone which were substituted at the 3-hydroxy group by ester and ether functions. The compounds were evaluated in vitro for their activity against the growth of Plasmodium falciparum, the malaria causing parasite. All the compounds showed potent activity, with IC(50) values in the range of 1.

Design and synthesis of novel imidazoline derivatives with potent antihyperglycemic activity in a rat model of type 2 diabetes.

Imidazoline derivatives have been reported to show antihyperglycemic activity in vivo. In the present study, we first showed that there was no correlation between the in vivo antidiabetic activity and the in vitro affinities for the I1/I2 binding sites for several substituted aryl imidazolines. Among these compounds, 2-(alpha-cyclohexyl-benzyl)-4,5-dihydro-1H-imidazole 2 exhibited potent antihyperglycemic properties.

Respective contributions of alpha-adrenergic and non-adrenergic mechanisms in the hypotensive effect of imidazoline-like drugs.

The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central alpha2-adrenoceptors (alpha2ARs). However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. This work aims (i) to check whether imidazoline-like drugs with no alpha2-adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an alpha2ARs agonist alpha-methylnoradrenaline (alpha-MNA).

Synthesis and pharmacological evaluation of imidazoline sites I1 and I2 selective ligands.

Several series of 2-aryl or heterocyclic-imidazoline compounds have been prepared and evaluated in vitro as imidazoline sites (I1 and I2) and alpha-adrenergic (alpha1 and alpha2) receptor ligands. Their pKi values indicate that linkage of the imidazoline moiety at the 2-position with an aromatic substituent dramatically decreases alpha-adrenergic affinity. I1 sites are more accessible by phenyl imidazolines substituted by a methyl or a methoxy group at the ortho or meta position.

[Synthesis and antidepressive activity study of aryl and heteroaryl carboxamides of benzylpiperazine].

The synthesis of 44 original amide derivatives of benzylpiperazine and some analogues of befuraline and piberaline is reported. All compounds have been tested as antidepressive agents. According to the tests, amides 1, 24 and mainly 31 (dihydrobefuraline) seem to provide elevated antidepressive activity.

3D-QSAR CoMFA study on imidazolinergic I(2) ligands: a significant model through a combined exploration of structural diversity and methodology.

Displaying an unprecedented structural diversity, 119 I(2) ligands, and their pK(i) values, were collected and submitted to a comparative molecular fields analysis (CoMFA) study. They were discerned into three structural subsets (A, B, C), to explore the I(2) 3D-QSARs from finite structural systems (A, B, C) to more complex ones (AB, AC, BC, ABC). In addition, various key steps of the CoMFA methology were explored.

Synthesis and structure-activity relationships of novel arylalkyl 4-benzyl piperazine derivatives as sigma site selective ligands.

Continuing our previous work that established that some chromones substituted by an aryl alkyl piperazino alkyl side chain are potent and selective sigma ligands and could be interesting in the treatment of psychosis, we synthesized 60 new compounds, replacing the chromone moiety by various cyclic systems. Many derivatives bind to the sigma sites in the nanomolar range and are generally selective in comparison with 5HT(1A) and the D(2) receptors. One of the most potent ligands of these series, 1-(2-naphthyl methyl)-4-benzyl piperazine 29, has been studied in various pharmacological tests.

Antipoliovirus structure-activity relationships of some aporphine alkaloids.

A series of 18 aporphinoids have been tested in vitro against human poliovirus. The aporphines (+)-glaucine fumarate (1), (+)-N-methyllaurotetanine (4), (+)-isoboldine (7), and (-)-nuciferine, HCl (10) were found to be active with selectivity indices > 14. The nature of the 1, 2-substituents of the isoquinoline moiety appeared to be critical for antipoliovirus activity.

[Study of plasma and hepatic hydrolysis of nitroxinil derivatives].

Seven esters derivatives of Nitroxinil were prepared and their structures were assigned by IR and 1H-NMR spectroscopy. The rate of plasma and hepatic hydrolysis were evaluated in vitro in sheep and rabbit. In view of this profile of activity, pivaloyl derivative merits evaluation, in vivo.

Synthesis and nematocidal activity of arylmercaptovinyltetrahydropyrimidines.

A set of mercaptovinyl tetrahydropyrimidines was synthesized in good yields by lithiation of 1,2-dimethyltetrahydropyrimidine with n-butyl lithium in tetrahydrofurane, followed by condensation with aromatic thioesters. Against three nematode genera, anthelminthic screening shows little activity; 2b and 2d were the most potent against Molinema dessetae.

[Diethyl benzylpiperazinomethyl and benzylpiperazinomethylbenzyl phosphonates as calcium inhibitors].

Two sets of phosphonic diethylester including a substituted benzylpiperazine moiety are synthesized. In spite of the spasmolytic or the calcium antagonistic potentialities of benzylpiperazine and phosphonic moieties, none of the six compounds, tested in vitro, exhibit any calcium antagonistic profile.

[The beta-adrenolytic activity of new arylmethyloxypropanolamine analogs of dioxadilol].

A series of arylmethyloxypropanolamines structurally related to Dioxadilol has been synthesized and tested for their beta adrenolytic activity. Only one compound, the benzofuranic derivative 3c, exhibited a similar activity as Dioxadilol but was less potent than propranolol.

Influence of the vinyl group on the calcium antagonistic activity of analogues of Fostedil.

Four aryl vinyl diethyl benzylphosphonates related to Fostedil were synthesized and evaluated for their in vitro calcium-inhibitory activity. None of these compounds exhibited any calcium antagonistic profile. Unlike a series of diethyl-styryl benzylphosphonates, previously described, the presence of two aromatic rings linked by a vinyl group did not improve the calcium antagonistic activity.

[Synthesis and pharmacology of structural analogs of tienilic acids].

Three structural analogs of tienilic acid were synthetized and evaluated for their diuretic activity in the rat. Two compounds are alpha substituted tienilic acid derivatives by an alkylated group. The third one is a conformationally restricted derivative through a cyclization process.

Inhibitory effect of new imidazole derivatives on the proliferation and nucleic acid synthesis of leukemic cells.

New derivatives of imidazothiazole and imidazobenzothiazole were tested in vitro for their potential antiproliferative activity. Four imidazobenzothiazole derivatives exhibited a cytotoxic activity against two leukemic cell lines, compound I being the most effective. Cell cycle kinetics studies showed that this drug delays the progression of cells from G1 to S and G2 M phases.

Biodistribution and metabolism in rats and mice of bucromarone.

The metabolism and disposition of bucromarone, labeled with 14C on the chromone group, has been investigated in C3H mice and Wistar rats. In separate experiments, animals received 4.4 mmol/kg, iv or po, [14C]bucromarone hydrochloride or succinate.

Synthesis and anthelminthic evaluation of 2-amidino-1,3,4-oxa and 1,3,4-thiadiazoles, structurally related to tetramisole.

N-(1,3,4-thiadiazol-2-yl) 1a-1k and N-(1,3,4-oxadiazol-2-yl-) amidines 2a-2g, N-(1,3-thiazol-2-yl) 3a, 3b and N-(1,3-benzothiazol-2-yl-)amidines 4a, 4b were synthesized and tested as anthelminthics, in vitro, against a free nematode (Rhabditis pseudoelongata), against infecting larvae of an intestinal parasite of rats (Nippostrongylus brasiliensis) and against infecting larvae of a filaria (Molinema dessetae).

Contribution of the diethyl phosphonate group to a first approach of calcium-inhibiting activity: study of a series of various substituted 2-phenylbenzothiazoles.

Eighteen substituted 2-phenyl benzothiazoles, nine of which are new, are described. Pharmacological investigation of these Fostedil analogues did not demonstrate the same calcium inhibitory properties shown by Fostedil. The enhancement induced by the diethyl phosphonate group is confirmed.

Synthesis and pharmacological study of new N-methyl 1,2,3-triazole derivatives of 2-cyano chromones.

The reaction of various 2-cyano chromones with diazomethane generated a series of 21 N-methyl triazoles, with a benzopyrone moiety and divided into three isomeric groups. The anti-inflammatory, psychotropic and anti-allergic effects of these new compounds were evaluated. The results obtained did not confirm their expected potentialities.

[Synthesis of 2-aryl benzothiazoles and research on its antiparasitic activity].

Several 2-aryl benzothiazoles (with phenyl, naphthyl, thienyl and some oxygenated heterocycles) were synthesized. The anti-parasitic properties of these compounds were evaluated, in vitro and in vivo, against one Nematode Nippostrongylus brasiliensis and, in vitro against two Protozoaires Entamoeba histolytica and Trichomonas vaginalis. Only two compounds exhibited, in vitro a low nematicidal activity.

[Dihydro-5,6-imidazo[2,1-b]thiazoles, dihydro-2,3-imidazo[2,1-b]benzothiazoles, analogs of levamisole].

New compounds containing 5,6-dihydro imidazo[2,1-b]thiazole, 2,3,5,6-tetrahydro imidazo[2,1-b]thiazole and 2,3-dihydro imidazo[2,1-b]benzothiazole rings, substituted by heterocycles analogue to chromones, were synthesized and screened against three nematodes, in vitro. The results indicate moderate anthelmintic properties, compared to levamisole; nevertheless, some products exhibit a significant degree of activity.

[In vivo and in vitro study of (N-piperidinomethyl)-2-chromanne on pre- and postsynaptic alpha-adrenoreceptors in the rat].

The alpha-adrenoceptors blocking effect of (N-piperidinomethyl)-2-chromanne was studied in vivo and in vitro in the rat. In the pithed rat, (N-piperidinomethyl)-2-chromanne (1 mg/kg i.v.

Interactions of some phenylindanedione anticoagulants with human serum albumin.

This study enabled us, to define the quantitative parameters of the interactions which give rise to the formation of complexes between five phenylindanediones and albumin or polymethacryate. The existence of three attachment sites were demonstrated, by which these ligands are bound to the macromolecule. The results from the thermodynamic study of this phenomenon, together with the information supplied by; various spectroscopic methods; the formation of a complex between a synthetic polymer carrying amine functions, and the study of ligands in the presence of surfactant, were all in agreement.

Diuretic properties of a new acylaryloxyacetic acid: 2-(2',3'-dichloro-4'-carboxymethylene oxybenzoyl)-chromone.

An acyldichlorophenoxyacetic acid was synthetized in which the acyl group was chromone nucleus. This compound was tested in dogs for its saluretic and diuretic properties in comparison with thienylic acid. It exhibited weak but significant diuretic activity in respect to the reference compound.