Réactions multicomposants de lawsone : vers des composés antiparasitaires et diversement actifs sur le plan biologique

Malaria and leishmaniasis are two vector-borne diseases (VBDs) caused by parasites (Plasmodium and Leishmania respectively), transmitted to humans, by infected insects. Numerous groups around the world are searching for molecules able to circumvent the problem of (multi)drug resistance of these pathogens. Naphthoquinone derivatives have attracted considerable attention in recent decades because of the antimalarial drug atovaquone, which consists of a 2-hydroxy-1,4-naphthoquinone (or lawsone) moiety. Atovaquone targets the cytochrome bc1 complex of Plasmodium falciparum (P.f.) in the parasite's mitochondria. This motif is also found in compounds active against Leishmania. So, we aim to design and develop compounds containing the lawsone motif that could be active against both parasites. For this purpose, we used multicomponent reactions for the elaboration of naphthoquinone-based compounds. We have studied and developed two multicomponent reactions involving lawsone: the domino and the Biginelli reaction. Optimal conditions for the domino reaction were successfully found. A series of 19 new naphthofuroquinones and 2 naphtho-enaminodiones, were synthesized. All compounds have been evaluated in vitro against P.f. and Leishmania donovani (L.d.). Six compounds are active against P.f. and three against L.d. The naphtho-enaminodiones were active on both targets. Selectivity indexes values (SI) were in the range 6-36. Next, lawsone was selected to undergo the Biginelli reaction by reacting with various ureas and benzaldehydes. The reaction was studied in solution and under mechanochemical activation. Only mechanochemistry led, in very good yields, to the unique linear compounds derived from the three-component coupling, the so-called "Biginelli-linear". These compounds were never described before. Expected dihydropyrimidones cyclic derivatives were never obtained. A first theoretical calculation approach was made to explain this result. Afterwards, a study was carried out to selectively obtain methylated derivatives of the enol function of Biginelli-linear series. We also paved the way for cyclization of this series to obtain. Activities against P.f. were low, the best being those of compounds derived from methylation (IC50 < 10 µM). All methylated derivatives are active against L.d., as 7/13 have IC50 < 2 µM, compared with the reference drug miltefosine (IC50 = 1.5 µM). All compounds mentioned herein were evaluated in silico against the two mitochondrial targets of P.f. bc1 and DHODH.Le paludisme et la leishmaniose sont deux maladies à transmission vectorielle (MVC) causées par des parasites (Plasmodium et Leishmania respectivement), transmises à l'homme par des insectes infectés. De nombreux groupes à travers le monde sont à la recherche de molécules capables de contourner le problème (multi)résistance aux médicaments, des pathogènes responsables. Les dérivés de la naphtoquinone ont attiré une attention considérable au cours des dernières décennies à cause de l'atovaquone, médicament antipaludique comportant un fragment 2-hydroxy-1,4-naphtoquinone (ou lawsone), qui cible le complexe cytochrome bc1 dans la mitochondrie de Plasmodium falciparum (P.f.). Ce motif est également présent dans des composés actifs contre Leishmania. Nous souhaitons donc concevoir et développer des composés possédant le motif lawsone qui pourraient être actifs contre ces deux parasites. Notre approche se concentre sur l'utilisation de réactions multicomposants pour construire des composés à base de naphtoquinone. Dans ce cadre, nous avons étudié et développé deux réactions multicomposants impliquant la lawsone : la réaction domino et la réaction de Biginelli. Les conditions optimales pour la réaction domino ont été recherchées avec succès. Une série de 19 nouvelles naphtofuroquinones et 2 naphto-énaminodiones a été élaborée. Tous les composés ont été évalués in vitro contre P.f. et Leishmania donovani (L.d.). Six composés sont actifs contre P.f. et trois contre L.d. Les deux naphto-énaminodiones sont actives sur les deux cibles. Les indices de sélectivité (SI) varient de 6 à 36. La réaction multicomposant de Biginelli, faisant intervenir la lawsone, diverses urées et des benzaldéhydes a été etudiée en solution et par mécanochimie. Seule, l'activation mécanochimique conduit avec des très bons rendements aux composés uniques issus du couplage des trois réactifs de manière linéaire, ainsi appelés " linéaires de Biginelli ". Ces composés n'ont jamais été décrits auparavant. Les dihydropyrimidinones de Biginelli, dérivés cycliques attendus n'ont pas pu être isolés. Pour expliquer ce résultat, une première approche de calcul théorique a été réalisée. Sur les composés linéaires de Biginelli, une étude a été menée pour obtenir de manière sélective les dérivés méthylés de la fonction énol. Nous avons également jeté les bases d'une réaction de cyclisation originale, conduisant à des carbamates. Tous les composés linéaires de cette série ont été évalués in vitro contre P.f. et L.d. Les activités contre P.f. sont faibles, les meilleurs étant les composés méthylés (IC50 < 10 µM). Contre L.d., tous les dérivés méthylés sont actifs, car 7/13 ont des IC50 < 2 µM, par comparaison avec la miltefosine (IC50 = 1.5 µM) qui est le médicament de référence. Tous les composés ont été également évalués in silico contre les deux cibles mitochondriales de P.f. bc1 et dihydroorotate déshydrogénase (DHODH)

Réactions multicomposants de lawsone : vers des composés antiparasitaires et diversement actifs sur le plan biologique

Malaria and leishmaniasis are two vector-borne diseases (VBDs) caused by parasites (Plasmodium and Leishmania respectively), transmitted to humans, by infected insects. Numerous groups around the world are searching for molecules able to circumvent the problem of (multi)drug resistance of these pathogens. Naphthoquinone derivatives have attracted considerable attention in recent decades because of the antimalarial drug atovaquone, which consists of a 2-hydroxy-1,4-naphthoquinone (or lawsone) moiety. Atovaquone targets the cytochrome bc1 complex of Plasmodium falciparum (P.f.) in the parasite's mitochondria. This motif is also found in compounds active against Leishmania. So, we aim to design and develop compounds containing the lawsone motif that could be active against both parasites. For this purpose, we used multicomponent reactions for the elaboration of naphthoquinone-based compounds. We have studied and developed two multicomponent reactions involving lawsone: the domino and the Biginelli reaction. Optimal conditions for the domino reaction were successfully found. A series of 19 new naphthofuroquinones and 2 naphtho-enaminodiones, were synthesized. All compounds have been evaluated in vitro against P.f. and Leishmania donovani (L.d.). Six compounds are active against P.f. and three against L.d. The naphtho-enaminodiones were active on both targets. Selectivity indexes values (SI) were in the range 6-36. Next, lawsone was selected to undergo the Biginelli reaction by reacting with various ureas and benzaldehydes. The reaction was studied in solution and under mechanochemical activation. Only mechanochemistry led, in very good yields, to the unique linear compounds derived from the three-component coupling, the so-called "Biginelli-linear". These compounds were never described before. Expected dihydropyrimidones cyclic derivatives were never obtained. A first theoretical calculation approach was made to explain this result. Afterwards, a study was carried out to selectively obtain methylated derivatives of the enol function of Biginelli-linear series. We also paved the way for cyclization of this series to obtain. Activities against P.f. were low, the best being those of compounds derived from methylation (IC50 < 10 µM). All methylated derivatives are active against L.d., as 7/13 have IC50 < 2 µM, compared with the reference drug miltefosine (IC50 = 1.5 µM). All compounds mentioned herein were evaluated in silico against the two mitochondrial targets of P.f. bc1 and DHODH.Le paludisme et la leishmaniose sont deux maladies à transmission vectorielle (MVC) causées par des parasites (Plasmodium et Leishmania respectivement), transmises à l'homme par des insectes infectés. De nombreux groupes à travers le monde sont à la recherche de molécules capables de contourner le problème (multi)résistance aux médicaments, des pathogènes responsables. Les dérivés de la naphtoquinone ont attiré une attention considérable au cours des dernières décennies à cause de l'atovaquone, médicament antipaludique comportant un fragment 2-hydroxy-1,4-naphtoquinone (ou lawsone), qui cible le complexe cytochrome bc1 dans la mitochondrie de Plasmodium falciparum (P.f.). Ce motif est également présent dans des composés actifs contre Leishmania. Nous souhaitons donc concevoir et développer des composés possédant le motif lawsone qui pourraient être actifs contre ces deux parasites. Notre approche se concentre sur l'utilisation de réactions multicomposants pour construire des composés à base de naphtoquinone. Dans ce cadre, nous avons étudié et développé deux réactions multicomposants impliquant la lawsone : la réaction domino et la réaction de Biginelli. Les conditions optimales pour la réaction domino ont été recherchées avec succès. Une série de 19 nouvelles naphtofuroquinones et 2 naphto-énaminodiones a été élaborée. Tous les composés ont été évalués in vitro contre P.f. et Leishmania donovani (L.d.). Six composés sont actifs contre P.f. et trois contre L.d. Les deux naphto-énaminodiones sont actives sur les deux cibles. Les indices de sélectivité (SI) varient de 6 à 36. La réaction multicomposant de Biginelli, faisant intervenir la lawsone, diverses urées et des benzaldéhydes a été etudiée en solution et par mécanochimie. Seule, l'activation mécanochimique conduit avec des très bons rendements aux composés uniques issus du couplage des trois réactifs de manière linéaire, ainsi appelés " linéaires de Biginelli ". Ces composés n'ont jamais été décrits auparavant. Les dihydropyrimidinones de Biginelli, dérivés cycliques attendus n'ont pas pu être isolés. Pour expliquer ce résultat, une première approche de calcul théorique a été réalisée. Sur les composés linéaires de Biginelli, une étude a été menée pour obtenir de manière sélective les dérivés méthylés de la fonction énol. Nous avons également jeté les bases d'une réaction de cyclisation originale, conduisant à des carbamates. Tous les composés linéaires de cette série ont été évalués in vitro contre P.f. et L.d. Les activités contre P.f. sont faibles, les meilleurs étant les composés méthylés (IC50 < 10 µM). Contre L.d., tous les dérivés méthylés sont actifs, car 7/13 ont des IC50 < 2 µM, par comparaison avec la miltefosine (IC50 = 1.5 µM) qui est le médicament de référence. Tous les composés ont été également évalués in silico contre les deux cibles mitochondriales de P.f. bc1 et dihydroorotate déshydrogénase (DHODH)

Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in Plasmodium falciparum: Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria

International audienceDespite many efforts, malaria remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by P. falciparum. Over the past decade, new essential pathways have been emerged to fight against malaria. Among them, epigenetic processes and mitochondrial metabolism appear to be important targets. This review will focus on recent evolutions concerning worldwide efforts to conceive, synthesize and evaluate new drug candidates interfering selectively and efficiently with these two targets and pathways. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties on DNA methyltransferases and HDAC’s for epigenetics, and on cytochrome bc1 and dihydroorotate dehydrogenase for mitochondrion

Synthesis of Novel artemisinin dimers and hybrids with other antimalarial agents.

International audienc

Unprecedented linear products by a mechanochemically activated Biginelli reaction using lawsone

International audienceThe Biginelli reaction, a crucial multicomponent reaction, was investigated involving 2-hydroxy-1,4-naphthoquinone (lawsone), p-substituted benzaldehydes, and ureas. Surprisingly, the classic Biginelli cyclized DHPM was not observed under various experimental conditions. Mechanochemical conditions, unlike traditional liquid phase conditions, led to the unprecedented formation of a series of ‘Biginelli-linear’ lawsone derivatives with high yields. The observed outcomes were consistent with DFT theoretical predictions, highlighting the preference for the Michael adduct under liquid conditions and the energetically implausible cyclization pathway for the classic DHPM compound. Additionally, the study achieved the novel cyclization of a ‘Biginelli-linear’ lawsone derivative into a cyclic carbamate for the first time

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

International audienceThe first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions