A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum-Infected Mouse Models from Structure–Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines

Manach, Claire Le; Paquet, Tanya; Brunschwig, Christel; Njoroge, Mathew; Han, Ze; Cabrera, Diego Gonzàlez; Bashyam, Sridevi; Dhinakaran, Rajkumar; Taylor, Dale; Reader, Janette; Botha, Mariette; Churchyard, Alisje; Lauterbach, Sonja; Coetzer, Thérèsa L.; Birkholtz, Lyn‐Marié; Meister, Stephan; Winzeler, Elizabeth A.; Waterson, David; Witty, Michael; Wittlin, Sergio; Jiménez-Díaz, María-Belén; Martínez, María Santos; Ferrer, Santiago; Angulo-Barturen, Íñigo; Street, Leslie J.; Chibale, Kelly

doi:10.1021/acs.jmedchem.5b01605

Cited by 36 publications

(18 citation statements)

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“…15 In a more recent paper, further expansion of SAR based on modifications to the imidazopyridazine core aimed at improving pharmacokinetics (PK), in vivo efficacy and selectivity over hERG were reported. 16 This led to the identification of the pyrazolopyridine analogue in which the two substituents in compound 2 were retained. Despite being able to completely cure P. berghei-infected mice at 4 × 50 mg kg −1 , the scaffold-hoped analogue still exhibited a hERG liability and poor solubility.…”

Section: Introductionmentioning

confidence: 99%

Antiplasmodial imidazopyridazines: structure–activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles

et al. 2018

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Section: Introductionmentioning

confidence: 99%

Antiplasmodial imidazopyridazines: structure–activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles

et al. 2018

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“…Cytochrome P450 (CYP450) inhibition studies (CYP2D6, CYP2C9, and CYP3A4/5) were carried out with pooled human liver microsomes under the conditions described in Walsky and Obach (31). Metabolite identification was performed by LC-MS/MS, as described in Le Manach et al (32), with a Phenomenex Kinetex PFP (pentafluorophenyl) column (2.1 mm by 100 mm, 2.6-m particle size) using microsomal incubations, incubations in hepatocytes from the hepatocyte stability assay, and in vivo mouse PK samples.…”

Section: Methodsmentioning

confidence: 99%

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria

Brunschwig

Lawrence

Taylor

et al. 2018

Antimicrob Agents Chemother

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The 2-aminopyridine MMV048 was the first drug candidate inhibiting phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant and clinical isolates. Excellent antiplasmodial activity translated into high efficacy in and humanized NOD-γ mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.

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“…However, they are mostly known for their anticancer [ 7 ] and antimicrobial [ 8 ] activities. Also, pyridine derivatives, including those bearing various heterocyclic nuclei, have shown potent pharmacological properties, including antifungal [ 9 , 10 ], antitubercular [ 11 ], antimalarial [ 12 ], antibacterial [ 13 ], antimicrobial [ 14 ], or insecticide [ 15 ]. We report here the synthesis of new 1,3,4-thiadiazoles, 5-arylazothiazoles, and pyridines containing 1,2,3-triazole moiety.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Some New 1,3,4-Thiadiazole, Thiazole and Pyridine Derivatives Containing 1,2,3-Triazole Moiety

2017

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In this study, 1-(5-Methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethan-1-one, was reacted with Thiosemicarbazide, alkyl carbodithioate and benzaldehyde to give thiosemicarbazone, alkylidenehydrazinecarbodithioate and 3-phenylprop-2-en-1-one-1,2,3-triazole derivatives. The 1,3,4-thiadiazole derivatives containing the 1,2,3-triazole moiety were obtained via reaction of alkylidenecarbodithioate with hydrazonoyl halides. Also, hydrazonoyl halides were reacted with thiosemicarbazone and pyrazolylthioamide to give 1,3-thiazoles derivatives. Subsequently, 3-phenyl-2-en-1-one was used to synthesize substituted pyridines and substituted nicotinic acid ester. The latter was converted to its azide compound which was reacted with aromatic amines and phenol to give substituted urea and phenylcarbamate containing 1,2,3-triazole moiety. The newly synthesized compounds were established by elemental analysis, spectral data and alternative synthesis whenever possible.

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A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum-Infected Mouse Models from Structure–Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines

Cited by 36 publications

References 20 publications

Antiplasmodial imidazopyridazines: structure–activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles

Antiplasmodial imidazopyridazines: structure–activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria

Synthesis of Some New 1,3,4-Thiadiazole, Thiazole and Pyridine Derivatives Containing 1,2,3-Triazole Moiety

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