Synthesis and Structure−Activity Relationships of Imidazopyridine/Pyrimidine‐ and Furopyridine‐Based Anti‐infective Agents against Trypanosomiases

Silva, Daniel G.; Junker, Anna; Melo, Shaiani Maria Gil de; Fumagalli, Fernando; Gillespie, J. Robert; Molasky, Nora; Buckner, Frederick S.; Matheeussen, An; Caljon, Guy; Maes, Louis; Emery, Flávio da Silva

doi:10.1002/cmdc.202000616

Cited by 18 publications

(4 citation statements)

References 29 publications

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“…According to the literature, there is evidence that 6,5-fused heterocyclic compounds exhibit a wide range of biological activity, including antiprotozoal activity [52,53]. In addition, the involvement of amino [54], amide [55], and pyrimidine [56,57] moieties in potent antiprotozoal hit compounds is indubitable. Thus, pyrimidine, amino, and amide groups embodied in the studied 6,5-fused heterocyclic compounds (X and Y) might have contributed to the observed antiprotozoal activities.…”

Section: Resultsmentioning

confidence: 99%

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Dize,

Tali,

Ngansop

et al. 2024

Future Pharmacology

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Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR]) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y, and Z) and one K+ channel blocker (E4031) were screened for their inhibitory effects on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. A resazurin assay was used to assess the antitrypanosomal and antileishmanial activities of the test compounds, whereas the antiplasmodial activity was evaluated through the SYBR Green I test. Moreover, the cytotoxicities of the test compounds were evaluated in Vero, Raw 264.7, and HepG-2 cells using a resazurin-based test, while their pharmacokinetic properties were predicted using the online tool, pkCSM. As a result, compound Y exhibited selective (selectivity index range: from 2.69 to >61.4; Vero, Raw 264.7, and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC50: 12.4 µM), amastigotes (IC50: 4.28 µM), P. falciparum (IC50: 0.028 µM), and T. brucei brucei (IC50: 0.81 µM). In addition, compound X inhibited the growth of P. falciparum (IC50: 0.0052 µM) and T. brucei brucei (IC50: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug likeness scores, as none of the criteria for Lipinski’s rule were violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support the discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K+ channel blockers and DHFR inhibitors.

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Section: Resultsmentioning

confidence: 99%

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Dize,

Tali,

Ngansop

et al. 2024

Future Pharmacology

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“…These were prepared via an analogous method, starting with a condensation–cyclization of the appropriate α-bromoketone 1 and aminopyridine 6 to give the imidazopyridine core 7 . A Mannich reaction allowed the aminoalkylations necessary for the imidazopyridine derivatives 9 ; , some anilines that were used in this reaction ( 8 ) were alkylated prior to the Mannich step (see Supporting Information - Chemistry).…”

Section: Resultsmentioning

confidence: 99%

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus

Klug,

Tse,

Silva

et al. 2023

ACS Infect. Dis.

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Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium ( ). Of the 18 compounds tested (at 32 μg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure–activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.

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“…The synthesis of the pyrimidine ring is the process for developing novel pyrimidine scaffold, which should have potential bioactive properties [4,15]. There are various approaches to synthesizing pyrimidine compounds, each with its own set of benefits and applications.…”

Section: Synthetic Methods Of Pyrimidinesmentioning

confidence: 99%

“…Among these isomers, pyrimidines are the most regularly found diazine isomer and the focus of this review. Because of its distinct structure, pyrimidine leads to a wide range of medical and synthetic applications described later [13][14][15].…”

Section: Introduction 1| Chemistry Of Pyrimidine and Its Derivativesmentioning

confidence: 99%

A review on pyrimidine‐based derivatives: Synthesis and their biological application

Islam,

Akter

et al. 2024

Journal of Heterocyclic Chem

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Pyrimidine‐based derivatives have attracted a lot of interest in heterocyclic chemistry due to its versatile structure and diverse biological activities. This study provides a comprehensive overview of synthetic strategy of different pyrimidine ring and highlights their biological importance. In this article, we start off by going through the fundamental procedures for the synthesis of pyrimidine scaffolds, including both conventional and contemporary synthetic techniques. These works cover a range of therapeutic domains, such as effects that are anticancer, antibacterial, antiviral, anti‐inflammatory, antioxidant, antimalarial, and so on. Moreover, we have summarized with a discussion of future prospects and challenges in the field of pyrimidine heterocyclic chemistry. This thorough review is a significant resource for researchers in medicinal chemistry and related fields since it offers insightful information about the synthetic methods and biological applications of pyrimidine‐based derivatives.

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Synthesis and Structure−Activity Relationships of Imidazopyridine/Pyrimidine‐ and Furopyridine‐Based Anti‐infective Agents against Trypanosomiases

Cited by 18 publications

References 29 publications

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus

A review on pyrimidine‐based derivatives: Synthesis and their biological application

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