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

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions

International audienceAn antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules:Synthesis, electrochemical and SAR study

International audienceTo study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin

8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 mu M range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 mu M) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 mu M), slightly lower than the one of miltefosine (IC50 = 4.3 mu M). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 mu M) and selective (SI = >313 to 550) molecules toward T brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 mu M). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTRI), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V

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

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

Synthesis, characterization, and antileishmanial activity of neutral N-heterocyclic carbenes gold(I) complexes

International audienceA series of five new mononuclear neutral gold(I) complexes containing N-heterocyclic carbenes (NHCs) was synthesized and fully characterized by spectroscopic methods. The X-ray structures of four complexes are presented. These gold(I) complexes together with four other neutral gold(I)-NHC complexes previously described were evaluated in vitro against Leishmania infantum promastigotes and axenic amastigotes. Moreover, their cytotoxicity was assessed on the murine macrophages J774A.1. Except one complex (10), eight gold(I)-NHC-Cl complexes show potent activity against the pathological relevant form of L. infantum amastigote with IC50 in the low micromolar and submicromolar range and five of them exhibit a SI close to 10. The lead-complex 11 displays a very high and selective activity (IC50 = 190 nM, SI = 40.29) and constitutes the best promising gold(I)-based drug of this series

Synthesis, Characterization, and Antileishmanial Activity of Neutral Gold(I) Complexes with N-heterocyclic Carbene Ligands Bearing Sulfur-Containing Side Arms

International audienceWith an estimated annual incidence of one million cases, leishmaniasis is one of the top five vector-borne diseases. Currently available medical treatments involve side effects, including toxicity, nonspecific targeting, and resistance development. Thus, new antileishmanial chemical entities are of the utmost importance to fight against this disease. We have shown in previous studies that gold(I) complexes bearing N-heterocyclic carbene (NHC) ligands with nitrogen- or sulfur-containing side arms have interesting biological activities in the field of cancer, malaria and leishmaniasis. The present study evaluates the in vitro antileishmanial effects on L. infantum axenic amastigotes and their cytotoxicity for the human THP1 cell line of a new family of six new imidazolium salts and their corresponding neutral (NHC)AuICl complexes. All new compounds have been characterized by classical analytical methods, and five gold complexes have been analyzed by X-ray structure determinations. We showed that one proligand has moderate activity (IC50 = 8.24 μM) while four of the six gold complexes have IC50 values in the low or sub μM range (0.15–1.3 μM), including three with selectivity index (SI) values between 46 and 108. These results suggest remarkable leishmanicidal activity in vitro for three new neutral (NHC)Au(I)Cl complexes, making them candidates for further in vivo studies, which are under investigation