Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.
Identifieur interne : 000731 ( Main/Exploration ); précédent : 000730; suivant : 000732Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.
Auteurs : Badr Jismy [France] ; Abdelkarim El Qami [Maroc] ; Anja Pišlar [Slovénie] ; Rok Frlan [Slovénie] ; Janko Kos [Slovénie] ; Stanislav Gobec [Slovénie] ; Damijan Knez [Slovénie] ; Mohamed Abarbri [France]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2021.
Descripteurs français
- KwdFr :
- Antiparkinsoniens (composition chimique), Antiparkinsoniens (pharmacologie), Antiparkinsoniens (synthèse chimique), Bibliothèques de petites molécules (pharmacocinétique), Bibliothèques de petites molécules (synthèse chimique), Bromures (composition chimique), Complexes de coordination (composition chimique), Humains (MeSH), Indazoles (composition chimique), Indazoles (pharmacocinétique), Indazoles (synthèse chimique), Inhibiteurs de la monoamine oxydase (pharmacocinétique), Inhibiteurs de la monoamine oxydase (synthèse chimique), Liaison aux protéines (MeSH), Monoamine oxidase (métabolisme), Métaux (composition chimique), Neuroblastome (traitement médicamenteux), Neuroprotecteurs (pharmacocinétique), Neuroprotecteurs (synthèse chimique), Relation structure-activité (MeSH), Simulation de docking moléculaire (MeSH), Tyramine (composition chimique).
- MESH :
- composition chimique : Antiparkinsoniens, Bromures, Complexes de coordination, Indazoles, Métaux, Tyramine.
- métabolisme : Monoamine oxidase.
- pharmacocinétique : Bibliothèques de petites molécules, Indazoles, Inhibiteurs de la monoamine oxydase, Neuroprotecteurs.
- pharmacologie : Antiparkinsoniens.
- synthèse chimique : Antiparkinsoniens, Bibliothèques de petites molécules, Indazoles, Inhibiteurs de la monoamine oxydase, Neuroprotecteurs.
- traitement médicamenteux : Neuroblastome.
- Humains, Liaison aux protéines, Relation structure-activité, Simulation de docking moléculaire.
English descriptors
- KwdEn :
- Antiparkinson Agents (chemical synthesis), Antiparkinson Agents (chemistry), Antiparkinson Agents (pharmacology), Bromides (chemistry), Coordination Complexes (chemistry), Humans (MeSH), Indazoles (chemical synthesis), Indazoles (chemistry), Indazoles (pharmacokinetics), Metals (chemistry), Molecular Docking Simulation (MeSH), Monoamine Oxidase (metabolism), Monoamine Oxidase Inhibitors (chemical synthesis), Monoamine Oxidase Inhibitors (pharmacokinetics), Neuroblastoma (drug therapy), Neuroprotective Agents (chemical synthesis), Neuroprotective Agents (pharmacokinetics), Protein Binding (MeSH), Small Molecule Libraries (chemical synthesis), Small Molecule Libraries (pharmacokinetics), Structure-Activity Relationship (MeSH), Tyramine (chemistry).
- MESH :
- chemical , chemical synthesis : Antiparkinson Agents, Indazoles, Monoamine Oxidase Inhibitors, Neuroprotective Agents, Small Molecule Libraries.
- chemical , chemistry : Antiparkinson Agents, Bromides, Coordination Complexes, Indazoles, Metals, Tyramine.
- chemical , metabolism : Monoamine Oxidase.
- chemical , pharmacokinetics : Indazoles, Monoamine Oxidase Inhibitors, Neuroprotective Agents, Small Molecule Libraries.
- chemical , pharmacology : Antiparkinson Agents.
- drug therapy : Neuroblastoma.
- Humans, Molecular Docking Simulation, Protein Binding, Structure-Activity Relationship.
Abstract
Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively inhibited human MAO-B isoform in a reversible and competitive manner as confirmed by kinetic experiments and docking studies. Selected derivatives were not cytotoxic to neuroblastoma SH-SY5Y cells. Moreover, analogue 4i protected human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced cell death, which confirms the applicability of the pyrimido[1,2-b]indazoles as potential antiparkinsonian agents.
DOI: 10.1016/j.ejmech.2020.112911
PubMed: 33071056
Affiliations:
Links toward previous steps (curation, corpus...)
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Le document en format XML
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Avenue Monge Faculté des Sciences, Parc de Grandmont, 37200, Tours, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratoire de Physico-Chimie des Matériaux et des Electrolytes pour L'Energie (PCM2E), EA 6299. Avenue Monge Faculté des Sciences, Parc de Grandmont, 37200, Tours</wicri:regionArea><placeName><region type="region" nuts="2">Centre-Val de Loire</region><region type="old region" nuts="2">Région Centre</region><settlement type="city">Tours</settlement></placeName></affiliation></author><author><name sortKey="El Qami, Abdelkarim" sort="El Qami, Abdelkarim" uniqKey="El Qami A" first="Abdelkarim" last="El Qami">Abdelkarim El Qami</name><affiliation wicri:level="1"><nlm:affiliation>Département de Chimie Université Hassan II de Casablanca, Laboratoire de Chimie Physique et de Chimie Bioorganique, URAC 22, BP 146, 28800, Mohammedia, Morocco.</nlm:affiliation><country xml:lang="fr">Maroc</country><wicri:regionArea>Département de Chimie Université Hassan II de Casablanca, Laboratoire de Chimie Physique et de Chimie Bioorganique, URAC 22, BP 146, 28800, Mohammedia</wicri:regionArea><wicri:noRegion>Mohammedia</wicri:noRegion></affiliation></author><author><name sortKey="Pislar, Anja" sort="Pislar, Anja" uniqKey="Pislar A" first="Anja" last="Pišlar">Anja Pišlar</name><affiliation wicri:level="1"><nlm:affiliation>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia.</nlm:affiliation><country xml:lang="fr">Slovénie</country><wicri:regionArea>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana</wicri:regionArea><wicri:noRegion>Ljubljana</wicri:noRegion></affiliation></author><author><name sortKey="Frlan, Rok" sort="Frlan, Rok" uniqKey="Frlan R" first="Rok" last="Frlan">Rok Frlan</name><affiliation wicri:level="1"><nlm:affiliation>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia.</nlm:affiliation><country xml:lang="fr">Slovénie</country><wicri:regionArea>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana</wicri:regionArea><wicri:noRegion>Ljubljana</wicri:noRegion></affiliation></author><author><name sortKey="Kos, Janko" sort="Kos, Janko" uniqKey="Kos J" first="Janko" last="Kos">Janko Kos</name><affiliation wicri:level="1"><nlm:affiliation>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia; Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000, Ljubljana, Slovenia.</nlm:affiliation><country xml:lang="fr">Slovénie</country><wicri:regionArea>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia; Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000, Ljubljana</wicri:regionArea><wicri:noRegion>Ljubljana</wicri:noRegion></affiliation></author><author><name sortKey="Gobec, Stanislav" sort="Gobec, Stanislav" uniqKey="Gobec S" first="Stanislav" last="Gobec">Stanislav Gobec</name><affiliation wicri:level="1"><nlm:affiliation>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia.</nlm:affiliation><country xml:lang="fr">Slovénie</country><wicri:regionArea>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana</wicri:regionArea><wicri:noRegion>Ljubljana</wicri:noRegion></affiliation></author><author><name sortKey="Knez, Damijan" sort="Knez, Damijan" uniqKey="Knez D" first="Damijan" last="Knez">Damijan Knez</name><affiliation wicri:level="1"><nlm:affiliation>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia. Electronic address: damijan.knez@ffa.uni-lj.si.</nlm:affiliation><country xml:lang="fr">Slovénie</country><wicri:regionArea>University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana</wicri:regionArea><wicri:noRegion>Ljubljana</wicri:noRegion></affiliation></author><author><name sortKey="Abarbri, Mohamed" sort="Abarbri, Mohamed" uniqKey="Abarbri M" first="Mohamed" last="Abarbri">Mohamed Abarbri</name><affiliation wicri:level="3"><nlm:affiliation>Laboratoire de Physico-Chimie des Matériaux et des Electrolytes pour L'Energie (PCM2E), EA 6299. Avenue Monge Faculté des Sciences, Parc de Grandmont, 37200, Tours, France. Electronic address: mohamed.abarbri@univ-tours.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratoire de Physico-Chimie des Matériaux et des Electrolytes pour L'Energie (PCM2E), EA 6299. Avenue Monge Faculté des Sciences, Parc de Grandmont, 37200, Tours</wicri:regionArea><placeName><region type="region" nuts="2">Centre-Val de Loire</region><region type="old region" nuts="2">Région Centre</region><settlement type="city">Tours</settlement></placeName></affiliation></author></analytic><series><title level="j">European journal of medicinal chemistry</title><idno type="eISSN">1768-3254</idno><imprint><date when="2021" type="published">2021</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiparkinson Agents (chemical synthesis)</term><term>Antiparkinson Agents (chemistry)</term><term>Antiparkinson Agents (pharmacology)</term><term>Bromides (chemistry)</term><term>Coordination Complexes (chemistry)</term><term>Humans (MeSH)</term><term>Indazoles (chemical synthesis)</term><term>Indazoles (chemistry)</term><term>Indazoles (pharmacokinetics)</term><term>Metals (chemistry)</term><term>Molecular Docking Simulation (MeSH)</term><term>Monoamine Oxidase (metabolism)</term><term>Monoamine Oxidase Inhibitors (chemical synthesis)</term><term>Monoamine Oxidase Inhibitors (pharmacokinetics)</term><term>Neuroblastoma (drug therapy)</term><term>Neuroprotective Agents (chemical synthesis)</term><term>Neuroprotective Agents (pharmacokinetics)</term><term>Protein Binding (MeSH)</term><term>Small Molecule Libraries (chemical synthesis)</term><term>Small Molecule Libraries (pharmacokinetics)</term><term>Structure-Activity Relationship (MeSH)</term><term>Tyramine (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antiparkinsoniens (composition chimique)</term><term>Antiparkinsoniens (pharmacologie)</term><term>Antiparkinsoniens (synthèse chimique)</term><term>Bibliothèques de petites molécules (pharmacocinétique)</term><term>Bibliothèques de petites molécules (synthèse chimique)</term><term>Bromures (composition chimique)</term><term>Complexes de coordination (composition chimique)</term><term>Humains (MeSH)</term><term>Indazoles (composition chimique)</term><term>Indazoles (pharmacocinétique)</term><term>Indazoles (synthèse chimique)</term><term>Inhibiteurs de la monoamine oxydase (pharmacocinétique)</term><term>Inhibiteurs de la monoamine oxydase (synthèse chimique)</term><term>Liaison aux protéines (MeSH)</term><term>Monoamine oxidase (métabolisme)</term><term>Métaux (composition chimique)</term><term>Neuroblastome (traitement médicamenteux)</term><term>Neuroprotecteurs (pharmacocinétique)</term><term>Neuroprotecteurs (synthèse chimique)</term><term>Relation structure-activité (MeSH)</term><term>Simulation de docking moléculaire (MeSH)</term><term>Tyramine (composition chimique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiparkinson Agents</term><term>Indazoles</term><term>Monoamine Oxidase Inhibitors</term><term>Neuroprotective Agents</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiparkinson Agents</term><term>Bromides</term><term>Coordination Complexes</term><term>Indazoles</term><term>Metals</term><term>Tyramine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Monoamine Oxidase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Indazoles</term><term>Monoamine Oxidase Inhibitors</term><term>Neuroprotective Agents</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiparkinson Agents</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Antiparkinsoniens</term><term>Bromures</term><term>Complexes de coordination</term><term>Indazoles</term><term>Métaux</term><term>Tyramine</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Neuroblastoma</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Monoamine oxidase</term></keywords><keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Bibliothèques de petites molécules</term><term>Indazoles</term><term>Inhibiteurs de la monoamine oxydase</term><term>Neuroprotecteurs</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiparkinsoniens</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiparkinsoniens</term><term>Bibliothèques de petites molécules</term><term>Indazoles</term><term>Inhibiteurs de la monoamine oxydase</term><term>Neuroprotecteurs</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Neuroblastome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Molecular Docking Simulation</term><term>Protein Binding</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Liaison aux protéines</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively inhibited human MAO-B isoform in a reversible and competitive manner as confirmed by kinetic experiments and docking studies. Selected derivatives were not cytotoxic to neuroblastoma SH-SY5Y cells. Moreover, analogue 4i protected human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced cell death, which confirms the applicability of the pyrimido[1,2-b]indazoles as potential antiparkinsonian agents.</div></front></TEI><affiliations><list><country><li>France</li><li>Maroc</li><li>Slovénie</li></country><region><li>Centre-Val de Loire</li><li>Région Centre</li></region><settlement><li>Tours</li></settlement></list><tree><country name="France"><region name="Centre-Val de Loire"><name sortKey="Jismy, Badr" sort="Jismy, Badr" uniqKey="Jismy B" first="Badr" last="Jismy">Badr Jismy</name></region><name sortKey="Abarbri, Mohamed" sort="Abarbri, Mohamed" uniqKey="Abarbri M" first="Mohamed" last="Abarbri">Mohamed Abarbri</name></country><country name="Maroc"><noRegion><name sortKey="El Qami, Abdelkarim" sort="El Qami, Abdelkarim" uniqKey="El Qami A" first="Abdelkarim" last="El Qami">Abdelkarim El Qami</name></noRegion></country><country name="Slovénie"><noRegion><name sortKey="Pislar, Anja" sort="Pislar, Anja" uniqKey="Pislar A" first="Anja" last="Pišlar">Anja Pišlar</name></noRegion><name sortKey="Frlan, Rok" sort="Frlan, Rok" uniqKey="Frlan R" first="Rok" last="Frlan">Rok Frlan</name><name sortKey="Gobec, Stanislav" sort="Gobec, Stanislav" uniqKey="Gobec S" first="Stanislav" last="Gobec">Stanislav Gobec</name><name sortKey="Knez, Damijan" sort="Knez, Damijan" uniqKey="Knez D" first="Damijan" last="Knez">Damijan Knez</name><name sortKey="Kos, Janko" sort="Kos, Janko" uniqKey="Kos J" first="Janko" last="Kos">Janko Kos</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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