Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-<i>a</i>]pyridine Antileishmanial Pharmacophore
An antileishmanial structure–activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-<i>a</i>]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of <i>Leishmania don...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-08-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/15/8/998 |
| _version_ | 1797442886463127552 |
|---|---|
| author | Romain Paoli-Lombardo Nicolas Primas Sandra Bourgeade-Delmas Sébastien Hutter Alix Sournia-Saquet Clotilde Boudot Emilie Brenot Caroline Castera-Ducros Sophie Corvaisier Marc Since Aurélie Malzert-Fréon Bertrand Courtioux Alexis Valentin Pierre Verhaeghe Nadine Azas Pascal Rathelot Patrice Vanelle |
| author_facet | Romain Paoli-Lombardo Nicolas Primas Sandra Bourgeade-Delmas Sébastien Hutter Alix Sournia-Saquet Clotilde Boudot Emilie Brenot Caroline Castera-Ducros Sophie Corvaisier Marc Since Aurélie Malzert-Fréon Bertrand Courtioux Alexis Valentin Pierre Verhaeghe Nadine Azas Pascal Rathelot Patrice Vanelle |
| author_sort | Romain Paoli-Lombardo |
| collection | DOAJ |
| description | An antileishmanial structure–activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-<i>a</i>]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of <i>Leishmania donovani</i> and <i>L. infantum,</i> the best compounds were tested against the intracellular amastigote stage of <i>L. infantum</i> and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-<i>a</i>]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC<sub>50</sub> > 100 µM) associated with a good activity against the intracellular amastigote stage of <i>L. infantum</i> (EC<sub>50</sub> = 3.7 µM <i>versus</i> 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T<sub>1/2</sub> > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model. |
| first_indexed | 2024-03-09T12:48:05Z |
| format | Article |
| id | doaj.art-83013cdfb1b946f190f6b3a926203f86 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T12:48:05Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-83013cdfb1b946f190f6b3a926203f862023-11-30T22:10:27ZengMDPI AGPharmaceuticals1424-82472022-08-0115899810.3390/ph15080998Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-<i>a</i>]pyridine Antileishmanial PharmacophoreRomain Paoli-Lombardo0Nicolas Primas1Sandra Bourgeade-Delmas2Sébastien Hutter3Alix Sournia-Saquet4Clotilde Boudot5Emilie Brenot6Caroline Castera-Ducros7Sophie Corvaisier8Marc Since9Aurélie Malzert-Fréon10Bertrand Courtioux11Alexis Valentin12Pierre Verhaeghe13Nadine Azas14Pascal Rathelot15Patrice Vanelle16CNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, FranceCNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, FranceUMR 152 PHARMA-DEV, IRD, UPS, Université de Toulouse, 31062 Toulouse, FranceIHU Méditerranée Infection, UMR VITROME-Tropical Eukaryotic Pathogens, Aix Marseille University, 19–21 Boulevard Jean Moulin, 13005 Marseille, FranceCNRS, UPS, LCC-CNRS, Université de Toulouse, 31077 Toulouse, FranceUMR Inserm 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, Université de Limoges, 2 Rue Du Dr. Marcland, 87025 Limoges, FranceUMR Inserm 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, Université de Limoges, 2 Rue Du Dr. Marcland, 87025 Limoges, FranceCNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, FranceUNICAEN, CERMN, Normandie University, 14000 Caen, FranceUNICAEN, CERMN, Normandie University, 14000 Caen, FranceUNICAEN, CERMN, Normandie University, 14000 Caen, FranceUMR Inserm 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, Université de Limoges, 2 Rue Du Dr. Marcland, 87025 Limoges, FranceUMR 152 PHARMA-DEV, IRD, UPS, Université de Toulouse, 31062 Toulouse, FranceCNRS, UPS, LCC-CNRS, Université de Toulouse, 31077 Toulouse, FranceIHU Méditerranée Infection, UMR VITROME-Tropical Eukaryotic Pathogens, Aix Marseille University, 19–21 Boulevard Jean Moulin, 13005 Marseille, FranceCNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, FranceCNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, FranceAn antileishmanial structure–activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-<i>a</i>]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of <i>Leishmania donovani</i> and <i>L. infantum,</i> the best compounds were tested against the intracellular amastigote stage of <i>L. infantum</i> and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-<i>a</i>]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC<sub>50</sub> > 100 µM) associated with a good activity against the intracellular amastigote stage of <i>L. infantum</i> (EC<sub>50</sub> = 3.7 µM <i>versus</i> 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T<sub>1/2</sub> > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model.https://www.mdpi.com/1424-8247/15/8/998Imidazo[1,2-<i>a</i>]pyridinenitroaromaticnitroreductases<i>Leishmania</i> spp.structure-activity relationshipsthermodynamic solubility |
| spellingShingle | Romain Paoli-Lombardo Nicolas Primas Sandra Bourgeade-Delmas Sébastien Hutter Alix Sournia-Saquet Clotilde Boudot Emilie Brenot Caroline Castera-Ducros Sophie Corvaisier Marc Since Aurélie Malzert-Fréon Bertrand Courtioux Alexis Valentin Pierre Verhaeghe Nadine Azas Pascal Rathelot Patrice Vanelle Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-<i>a</i>]pyridine Antileishmanial Pharmacophore Pharmaceuticals Imidazo[1,2-<i>a</i>]pyridine nitroaromatic nitroreductases <i>Leishmania</i> spp. structure-activity relationships thermodynamic solubility |
| title | Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-<i>a</i>]pyridine Antileishmanial Pharmacophore |
| title_full | Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-<i>a</i>]pyridine Antileishmanial Pharmacophore |
| title_fullStr | Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-<i>a</i>]pyridine Antileishmanial Pharmacophore |
| title_full_unstemmed | Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-<i>a</i>]pyridine Antileishmanial Pharmacophore |
| title_short | Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-<i>a</i>]pyridine Antileishmanial Pharmacophore |
| title_sort | improving aqueous solubility and in vitro pharmacokinetic properties of the 3 nitroimidazo 1 2 i a i pyridine antileishmanial pharmacophore |
| topic | Imidazo[1,2-<i>a</i>]pyridine nitroaromatic nitroreductases <i>Leishmania</i> spp. structure-activity relationships thermodynamic solubility |
| url | https://www.mdpi.com/1424-8247/15/8/998 |
| work_keys_str_mv | AT romainpaolilombardo improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT nicolasprimas improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT sandrabourgeadedelmas improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT sebastienhutter improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT alixsourniasaquet improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT clotildeboudot improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT emiliebrenot improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT carolinecasteraducros improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT sophiecorvaisier improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT marcsince improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT aureliemalzertfreon improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT bertrandcourtioux improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT alexisvalentin improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT pierreverhaeghe improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT nadineazas improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT pascalrathelot improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore AT patricevanelle improvingaqueoussolubilityandinvitropharmacokineticpropertiesofthe3nitroimidazo12iaipyridineantileishmanialpharmacophore |