Jean-Pierre Galy

In Vitro Activities of Position 2 Substitution-Bearing 6-Nitro- and 6-Amino-Benzothiazoles and Their Corresponding Anthranilic Acid Derivatives against Leishmania infantum and Trichomonas vaginalis

ABSTRACT 6-Nitro- and 6-amino-benzothiazoles bearing different chains in position 2 and their corresponding anthranilic acid derivatives were investigated for their in vitro antiparasitic properties against parasites of the species Leishmania infantum and Trichomonas vaginalis compared to their toxicity towards human monocytes. Biological investigations established that the antiprotozoal properties depended greatly on the chemical structure of the position 2 substitution-bearing group. Compound C1, 2-[(2-chloro-benzothiazol-6-yl) amino] benzoic acid, demonstrated an interesting antiproliferative activity towards parasites of the species T. vaginalis, while compound C11, 2-({2-[(2-hydroxyethyl) amino]-benzothiazol-6-yl} amino) benzoic acid, exhibited a promising activity against parasites of the species L. infantum in their intracellular amastigote form. Additional experiments established that compound C11, which was poorly toxic against the promastigote and the extracellular amastigote forms of the parasite, could improve host-protective mechanisms against Leishmania by preventing parasite internalization by macrophages and stimulating NO production, by means of a mechanism synergistically enhanced by the presence of gamma interferon.

In Vitro Activities of 7-Substituted 9-Chloro and 9-Amino-2-Methoxyacridines and Their Bis- and Tetra-Acridine Complexes against Leishmania infantum

ABSTRACT 9-Chloro and 9-amino-2-methoxyacridines bearing different substituents in position 7, as well as their corresponding unsubstituted dimeric and tetrameric complexes, were investigated for in vitro antiproliferative properties against Leishmania infantum compared to toxicity towards human monocytes. The results clearly confirmed that several compounds of the 2-methoxyacridine series, together with their corresponding dimeric and tetrameric derivatives, had strong in vitro antiparasitic properties. Antileishmanial activity was shown to depend on the nature of both 7- and 9-substituted groups in monoacridines, while it varied according to the nature of the 9-substituted group and the length of the linker among bis- and tetra-acridines. The effects of acridine derivatives on DNA synthesis raised the hypothesis that DNA metabolism constituted their main target in Leishmania promastigotes; however, secondary effects on other biochemical pathways, including protein and lipid metabolism, were observed, suggesting that acridine compounds could be considered multitarget drugs.

Some new 1-nitro acridine derivatives as antimicrobial agents

Abstract Some new 1-nitro acridine derivatives were prepared and characterized. These compounds were screened for evaluating their antimicrobial properties against Gram+ bacteria, Gram − bacteria, and mycobacteria as well as fungi. With reference to the results obtained, 1-nitro-4-aminoethylamine-9-alkylthioacridines must be considered as promising lead molecules.

Activity of benzothiazoles and chemical derivatives on Plasmodium falciparum

Malaria is a major health concern particularly in Africa which has about 90% of the worldwide annual clinical cases. The increasing number of drug-resistant Plasmodium falciparum justifies the search for new drugs in this field. Antimalarial activity of 2-substituted 6-nitro- and 6-amino-benzothiazoles and their anthranilic acids has been tested. An in vitro study has been performed on W2 and 3D7 strains of P. falciparum and on clinical isolates from malaria-infected patients. Toxicity has been assessed on THP1 human monocytic cells. For the most active drug candidates, the in vitro study was followed by in vivo assays on P. berghei-infected mice and by in vitro assays in order to determine the stage-dependency and the mechanism of action. Of 39 derivatives tested in vitro, 2 had specific antimalarial properties. Each compound was active on all stages of the parasite, but one was markedly active on mature schizonts, while the other was more active on young schizont forms. Both drugs were also active on mitochondrial membrane potential. In vivo data confirmed efficiency with a sustained decrease of parasitaemia. Products A12 and C7 may be considered as potential antimalarial worthy of further chemical and biological research.

Synthesis of new Bis- and Tetra-Acridines

A new series of bis- and tetra-acridines has been prepared from 4-(bromo-methyl)acridine; some of them exhibited encouraging in vitro cytotoxic activities against murine cell lines.

A Convenient Synthesis of N-Arylanthranilic Acids Using Ultrasonics in the Ullmann-Goldberg Condensation

Abstract Ultrasonics efficiently promotes the Ullmann-Goldberg condensation of 2-halogenobenzoic acids and primary aromatic amines to obtain various N-arylanthranilic acids.

Antimicrobial activity of 9-oxo and 9-thio acridines: Correlation with intercalation into DNA and effects on macromolecular biosynthesis

The antimicrobial activity of several new 9-acridinones and 9-thioalkylacridines towards Escherichia coli, Staphylococcus aureus, Mycobacterium smegmatis and Candida albicans was investigated. Minimal inhibitory, bactericidal and fungicidal concentrations were determined using a microplate assay which enabled inhibitory, bactericidal and fungicidal indices to be calculated. These indices facilitated structure/activity relationship studies. DNA-intercalating capability and DNA supercoiling inhibitory effects as well as inhibitory effects on macromolecular synthesis were determined. Results showed that intercalation into DNA, which is the mechanism of action usually postulated for acridines, cannot be correlated with the properties examined. However, inhibition of RNA synthesis may be involved in the antimicrobial activity of the drugs.

Thiazolo [5,4-α] acridines

The synthesis of thiazolo [5,4-α] acridines and acridin-9(10H)-ones by cyclisation of anthranilic acids is described. NMR (specially 1H NMR) was used to ascertain their ‘bent’ structure.

Synthesis, 1H and 13C NMR Study of Pyrazoles Derived from Chiral Cyclohexanones (3-Methylcyclohexanone, Menthone, Pulegone, Dihydrocarvone and Carvone)

The 1 H and 1 3 C chemical shifts of four tetrahydroindazoles (two of them existing as diastereomeric mixtures) and one aldazine were measured and assigned. These compounds were obtained from monoterpenic ketones (R)-(+)-3-methylcyclohexanone, (2S,5R)-(-)-menthone, (R)-(+)-pulegone, (5R)-(+)-dihydrocarvone, and (R)-(-)-carvone in a two-step procedure. The annular tautomerism in CDCl 3 solution was calculated and compared with ab initio calculations (B3LYP/6-31G * ).

Synthesis and crystallographic studies of new acridinic esters and amides: An efficient synthetic route to 4-methyl functionalized acridines

In order to open a new way in antitumor drugs research, an efficient synthetic route to mono functional 4-substitued acridine derivatives has been developed on the basis of direct electrophilic substitution of acridine. This method leads to a wide range of simple acridinic patterns that can be linked to various side chains. We present here the synthesis of two new families of acridine ester and amide derivatives, obtained from acridinic alcohol and amine respectively, with high yields. Some crystallographic aspects of one representative compound of each family are discussed.