In vitro and in vivo evaluation of the antimalarial MMV665831 and structural analogs

Ding, Sha; Fike, Katherine R.; Klemba, Michael; Carlier, Paul R.

doi:10.1016/j.bmcl.2020.127348

Cited by 3 publications

(7 citation statements)

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“…falciparum strains. While ester 27 was not active in vivo (mouse), compounds 28 – 30 revealed activity in mouse models of acute malaria even after oral application. , 29 and 30 are currently under preclinical evaluation and 32 is already used for the treatment of malaria patients. The structure and mode of action of 32 and chloroquine are very similar, but 32 has a longer plasma elimination half-life than chloroquine.…”

Section: Discussionmentioning

confidence: 57%

“…Some antimalarial drugs containing the 2-(aminomethyl)phenol substructure have already been reported in the literature. − Amodiaquine ( 32 ) containing this structural motif is used clinically for the therapy of malaria. , Some prototypes including amodiaquine are displayed in Figure . The compounds 27 – 30 were identified by screening of compound libraries and subsequent specific modifications.…”

Section: Discussionmentioning

confidence: 99%

“…Such a mechanism would certainly also result in high mammalian cytotoxicity and low selectivity for the desired target. Carlier and co-workers discussed this potential problem thoroughly for 27 . Since a homologous aminoethyl derivative was also active, they concluded that the antiplasmodial activity of 27 was not derived from an o -quinone methide intermediate.…”

Section: Discussionmentioning

confidence: 99%

“…Since a homologous aminoethyl derivative was also active, they concluded that the antiplasmodial activity of 27 was not derived from an o -quinone methide intermediate. Moreover, they reported a remarkable stability of the Mannich base under various conditions …”

Section: Discussionmentioning

confidence: 99%

“…6 : Colorless solid, mp 104 °C (ref : 104 °C), R f = 0.26 (CyHex/CH 2 Cl 2 20: 80), yield 2.71 g (13.1 mmol, 37%), C 12 H 14 O 3 (206.2). 1 H NMR (600 MHz, CDCl 3 ): δ (ppm) = 1.36 (s, 6H, 2 × CH 3 ), 1.83 (t, 3 J = 6.7 Hz, 2H, 3-CH 2 ), 2.75 (t, 3 J = 6.8 Hz, 2H, 4-CH 2 ), 6.32 (s, 1H, 8-CH), 7.21 (s, 1H, 5-CH), 9.66 (s, 1H, C H O), 11.07 (s, 1H, OH).…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

et al. 2021

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Herein, relationships between the structures of 1-aminoethyl-substituted chromenes and their antimalarial activities were thoroughly investigated. At first, the methyl moiety in the side chain was removed to eliminate chirality. The hydrogenation state of the benzopyran system, the position of the phenolic OH moiety, and the distance of the basic amino moiety toward both aromatic rings were varied systematically. 1-Benzopyran-5-ol 8b (IC50 = 10 nM), 1-benzopyran-7-ol 9c (IC50 = 38 nM), and the aminoalcohol 19c (IC50 = 17 nM) displayed antiplasmodial activity with IC50 values below 50 nM. To identify the mechanism of action, inhibition of three key enzymes by 9c was investigated. 9c was not able to reduce the number of Plasmodia in erythrocytes of mice. This low in vivo activity was explained by fast clearance from blood plasma combined with rapid biotransformation of 9c. Three main metabolites of 9c were identified by liquid chromatography–mass spectrometry (LC–MS) methods.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

et al. 2021

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Synthesis of Benzothiophene-3-carboxylic Esters by Palladium Iodide-Catalyzed Oxidative Cyclization–Deprotection–Alkoxycarbonylation Sequence under Aerobic Conditions

et al. 2022

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A palladium-catalyzed carbonylative approach to benzothiophene-3-carboxylic esters, starting from simple and readily available building blocks [2-(methylthio)phenylacetylenes, CO, an alcohol, and O 2 (from air)], is reported. The process is catalyzed by the simple PdI 2 /KI catalytic system to give the desired products in fair to high yields (57−83%). Interestingly, the reaction also works nicely in the ionic liquid BmimBF 4 as the solvent, with the possibility to recycle the catalytic system several times without appreciable loss of activity.

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Current Pharmaceutical Research on the Significant Pharmacophore Mannich bases in Drug Design

Yamali,

Gul,

Gul

2023

CTMC

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A multitude of distinct Mannich bases have been synthesized and evaluated as potential therapeutics for a wide variety of diseases and medical conditions, either in the form of prodrugs or as molecules that trigger a biological response from specific targets. The Mannich reaction has been utilized to enhance the biological activity of numerous compounds, resulting in notable progress in various areas such as anticonvulsant, antimalarial, anticancer, anti-inflammatory, antiproliferative, antibacterial, antimicrobial, antitubercular, antiprotozoal, topoisomerases I and II inhibition, α-glucosidase inhibition, carbonic anhydrase inhibition, as well as research related to anti-Alzheimer's disease and anti-Parkinson's disease. Bioactive semisynthetic Mannich bases derived from natural compounds such as chalcone, curcumin, and thymol have also been identified. Pharmaceutical compounds characterized by low solubility may encounter challenges related to their oral bioavailability, half-life, distribution within tissues, rapid metabolism, toxicity, and various other relevant variables. Mannich bases have the ability to undergo protonation under physiological circumstances, facilitating interactions between ligands and receptors, and enhancing their solubility in water. The experimental findings indicate that the solubility of Mannich base prodrugs is higher compared to that of the parent compound. The use of the multicomponent Mannich reaction has been established as a valuable synthetic methodology for the construction of multifunctional compounds through the application of diverse synthetic strategies under varying reaction conditions. The continuous investigation of synthetic techniques for Mannich reactions involves several approaches, such as employing protocols in aquatic environments, utilizing catalysts that are both biodegradable and reusable, exploring the use of ionic liquids, investigating solvent-free and/or catalyst-free media, and exploring reaction conditions involving microwave and ultrasound irradiation. Consequently, the Mannich reaction has emerged as a powerful technique in the field of medicinal chemistry. It is utilized for the creation of new chemical compounds that possess diverse and attractive biologic features. Additionally, this reaction is employed to alter the physicochemical properties of a potential drug candidate, thereby influencing its bioavailability, efficacy, and pharmacological activity. Due to their favorable bioactivities and synthesis techniques, Mannich bases remain a subject of ongoing attention in the field of medical and pharmaceutical chemistry.

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In vitro and in vivo evaluation of the antimalarial MMV665831 and structural analogs

Cited by 3 publications

References 30 publications

Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

Synthesis of Benzothiophene-3-carboxylic Esters by Palladium Iodide-Catalyzed Oxidative Cyclization–Deprotection–Alkoxycarbonylation Sequence under Aerobic Conditions

Current Pharmaceutical Research on the Significant Pharmacophore Mannich bases in Drug Design

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