Synthèse et activité anti-malaria de dérivés d'acridine (relation structure-activité)

Dans ce travail, 40 nouveaux dérivés de la 9-aminoacridine ont été synthétisés et caractérisés avec des rendements optimisables. Des stratégies de synthèse relativement faciles et non coûteuses ont été adoptées. Ces composés sont basés sur les noyaux 6-chloro-2-methoxy-9-aminoacridine ou 9-aminoacridine. Ils comprennent des chaînes latérales différentes (longueur et groupement terminal) sur la position 9' du noyau d'acridine. L'activité anti-malaria de ces composés est testée in vitro sur des souches P. falciparum sensibles à la CQ et des souches résistantes à la CQ. Afin de comprendre leur propriété anti-malaria, deux mécanismes proposés sont étudiés in vitro : l'inhibition de la formation de la b-hématine et l'inhibition de l'activité de topoisomerases par l'intercalation dans l'ADN. De plus, l'effet cytotoxique de ces composés est évalué in vitro sur les cellules KB (human epidermoid carcinoma).ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Spermine-NBD as fluorescent probe for studies of the polyamine transport system in Leishmania donovani

International audienceThis study describes the synthesis of fluorescent probes as potential substrates for the polyamine transport system (PTS) of Leishmania donovani. A competitive radioassay was used to determine the most efficient probe. We observed that the conjugate spermine-nitrobenzofurazan (Spm-NBD) was able to compete with [3H]-spermidine in L. donovani at a potent IC50 of 60 µM

Spermine-NBD as Fluorescent Probe for Studies of Polyamine Transport System in Leishmania Donovani

This study describes the synthesis of fluorescent probes as potential substrates for the polyamine transport system (PTS) of Leishmania donovani. A competitive radioassay was used to determine the most efficient probe. We observed that the conjugate spermine-nitrobenzofurazan (Spm-NBD) was able to compete with [3H]-spermidine in L. donovani at a relevant IC50 of 60 µM. </p

SYNTHESIS AND EVALUATION OF NEW OMEGA-BORONO-ALPHA-AMINOACIDS AS RAT LIVER ARGINASE INHIBITORS

International audienceRecent studies have demonstrated that arginase plays important roles in pathologies such as asthma or erectile dysfunctions. We have synthesized new omega-borono-alpha-amino acids that are analogues of the previously known arginase inhibitors S-(2-boronoethyl)-l-cysteine (BEC) and 2-amino-6-boronohexanoic acid (ABH) and evaluated them as inhibitors of purified rat liver arginase (RLA). In addition to the distance between the B(OH)(2) and the alpha-amino acid functions, the position of the sulfur atom in the side chain also appears as a key determinant for the interaction with the active site of RLA. Furthermore, substitution of the alkyl side chain of BEC by methyl groups and conformational restriction of ABH by incorporation of its side chain in a phenyl ring led to inactive compounds. These results suggest that subtle interactions govern the affinity of inhibitors for the active site of RLA.Recent studies have demonstrated that arginase plays important roles in pathologies such as asthma or erectile dysfunctions. We have synthesized new omega-borono-alpha-amino acids that are analogues of the previously known arginase inhibitors S-(2-boronoethyl)-l-cysteine (BEC) and 2-amino-6-boronohexanoic acid (ABH) and evaluated them as inhibitors of purified rat liver arginase (RLA). In addition to the distance between the B(OH)(2) and the alpha-amino acid functions, the position of the sulfur atom in the side chain also appears as a key determinant for the interaction with the active site of RLA. Furthermore, substitution of the alkyl side chain of BEC by methyl groups and conformational restriction of ABH by incorporation of its side chain in a phenyl ring led to inactive compounds. These results suggest that subtle interactions govern the affinity of inhibitors for the active site of RLA

NMR Characterization of the Influence of Zinc(II) Ions on the Structural and Dynamic Behavior of the New Delhi Metallo-β-Lactamase-1 and on the Binding with Flavonols as Inhibitors

International audienceNew Delhi metallo-β-lactamase-1 (NDM-1) has recently emerged as a global threat because of its ability to confer resistance to all common β-lactam antibiotics. Understanding the molecular basis of β-lactam hydrolysis by NDM is crucial for designing NDM inhibitors or β-lactams resistant to their hydrolysis. In this study, for the first time, NMR was used to study the influence of Zn(II) ions on the dynamic behavior of NDM-1. Our results highlighted that the binding of Zn(II) in the NDM-1 active site induced several structural and dynamic changes on active site loop 2 (ASL2) and L9 loops and on helix α2. We subsequently studied the interaction of several flavonols: morin, quercetin, and myricetin were identified as natural and specific inhibitors of NDM-1. Quercetin conjugates were also synthesized in an attempt to increase the solubility and bioavailability. Our NMR investigations on NDM-1/flavonol interactions highlighted that both Zn(II) ions and the residues of the NDM-1 ASL1, ASL2, and ASL4 loops are involved in the binding of flavonols. This is the first NMR interaction study of NDM-1/inhibitors, and the models generated using HADDOCK will be useful for the rational design of more active inhibitors, directed against NDM-1