Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 mu M) alongside good antileishmanial activities (IC50 = 1-2.1 mu M) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 mu M) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 mu M). Molecule 5, presenting a low reduction potential (E degrees = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies

Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.<br/

Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.<br/

Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide (LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access to Bioactive Backbones

Cyclic polymers display unique physicochemical and biological properties. However, their development is often limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from N-alkylated-N-carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF. This new method allows the unprecedented use of lysine-like monomers in REP to design bioactive macrocycles bearing pharmaceutical potential against Clostridioides difficile, a bacterium responsible for nosocomial infections

New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi

International audienceAn antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = −0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

Antikinetoplastid SAR study in 3-nitroimidazopyridine series:identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

International audienceTo study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = −0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

TDAE strategy : synthetic tools and pharmacomodulation uses

Ce travail est consacré au développement de la stratégie TDAE dans le cadre de la synthèse de nouveaux composés à visée thérapeutique. Dans une première partie, la pharmacomodulation d’un composé potentiellement ligand sélectif du récepteur 5-HT7 nous a conduit à développer une méthodologie d’addition et d’estérification séquentielle « one-pot » initiée par le TDAE. Par la suite, nous avons étendu la réactivité initiée par le TDAE aux réactions de substitution nucléophile de type 2 sur des électrophiles &#61537;-halogénoesters et &#61537;-halogénoamides en série nitrobenzylique. Cette méthodologie nous a permis de synthétiser différents 3-(2-nitrophényl)propanamides qui ont manifesté, pour certains, une activité analgésique significative chez la souris. La deuxième partie est consacrée à la synthèse de divers 3-phénylpropanamides et à l’évaluation de leur propriété analgésique. L’un des ces composés s’est révélé puissant mais modérément efficace par rapport à l’aspirine, que ce soit par voie injectable ou par voie orale. La troisième partie traite de la réactivité initiée par le TDAE sur le noyau 4-chloroquinazoline. Outre la mise en évidence de réactivités particulières liées aux caractères basique et nucléophile du TDAE, cette étude a montré la possibilité de réaliser des réactions de substitution nucléophile aromatique. La synthèse de diverses 4-benzyl-2-trichlorométhylquinazolines par cette méthodologie, s’inscrit dans une étude de pharmacomodulation de nouveaux agents antiplasmodiaux.This work is focused on the development of the TDAE strategy aiming at the preparation of new bioactive compounds. In a first part, the pharmacomodulation study of a potential 5-HT7 receptor ligand led us to develop a “one-pot” methodology of addition and sequential esterification initiated by the TDAE. Later, we extended the reactivity of carbanions generated by TDAE to type 2 nucleophilic substitution (SN2) reactions on various &#61537;-haloesters and &#61537;-haloamides in nitrobenzylic series. This methodology allowed us to synthesize different 3-(2-nitrophenyl)propanamides which expressed a significant analgesic activity on mice. The second part is dedicated to the synthesis of various 3-phenylpropanamide and the evaluation of their analgesic potentiality. One of those compounds appeared active but moderately effective with regard to aspirin, both by infusion or oral route. The third part concerns the TDAE-initiated reactivity with the 4-chloroquinazoline scaffold. In addition to the description of two particular reactivities related to its basic and nucleophilic characters, this study showed the possibility to carry out aromatic nucleophilic reactions (SNAr). The synthesis of several 4-benzyl-2-trichloromethylquinazolines using this original methodology was related to a program of new antiplasmodial agents pharmacomodulation

TDAE strategy : synthetic tools and pharmacomodulation uses

Ce travail est consacré au développement de la stratégie TDAE dans le cadre de la synthèse de nouveaux composés à visée thérapeutique. Dans une première partie, la pharmacomodulation d’un composé potentiellement ligand sélectif du récepteur 5-HT7 nous a conduit à développer une méthodologie d’addition et d’estérification séquentielle « one-pot » initiée par le TDAE. Par la suite, nous avons étendu la réactivité initiée par le TDAE aux réactions de substitution nucléophile de type 2 sur des électrophiles &#61537;-halogénoesters et &#61537;-halogénoamides en série nitrobenzylique. Cette méthodologie nous a permis de synthétiser différents 3-(2-nitrophényl)propanamides qui ont manifesté, pour certains, une activité analgésique significative chez la souris. La deuxième partie est consacrée à la synthèse de divers 3-phénylpropanamides et à l’évaluation de leur propriété analgésique. L’un des ces composés s’est révélé puissant mais modérément efficace par rapport à l’aspirine, que ce soit par voie injectable ou par voie orale. La troisième partie traite de la réactivité initiée par le TDAE sur le noyau 4-chloroquinazoline. Outre la mise en évidence de réactivités particulières liées aux caractères basique et nucléophile du TDAE, cette étude a montré la possibilité de réaliser des réactions de substitution nucléophile aromatique. La synthèse de diverses 4-benzyl-2-trichlorométhylquinazolines par cette méthodologie, s’inscrit dans une étude de pharmacomodulation de nouveaux agents antiplasmodiaux.This work is focused on the development of the TDAE strategy aiming at the preparation of new bioactive compounds. In a first part, the pharmacomodulation study of a potential 5-HT7 receptor ligand led us to develop a “one-pot” methodology of addition and sequential esterification initiated by the TDAE. Later, we extended the reactivity of carbanions generated by TDAE to type 2 nucleophilic substitution (SN2) reactions on various &#61537;-haloesters and &#61537;-haloamides in nitrobenzylic series. This methodology allowed us to synthesize different 3-(2-nitrophenyl)propanamides which expressed a significant analgesic activity on mice. The second part is dedicated to the synthesis of various 3-phenylpropanamide and the evaluation of their analgesic potentiality. One of those compounds appeared active but moderately effective with regard to aspirin, both by infusion or oral route. The third part concerns the TDAE-initiated reactivity with the 4-chloroquinazoline scaffold. In addition to the description of two particular reactivities related to its basic and nucleophilic characters, this study showed the possibility to carry out aromatic nucleophilic reactions (SNAr). The synthesis of several 4-benzyl-2-trichloromethylquinazolines using this original methodology was related to a program of new antiplasmodial agents pharmacomodulation

Evaluations objectives et subjectives d'une prothèse totale du genou adaptée aux femmes (résultat d'une étude pilote comparative de 30 cas implantés de façon bilatérale)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF