Structure–Property Optimization of a Series of Imidazopyridines for Visceral Leishmaniasis

Dichiara, Maria; Simpson, Quillon J.; Quotadamo, Antonio; Jalani, Hitesh B.; Huang, Anson X.; Millard, Caroline C.; Klug, Dana M.; Tse, Edwin G.; Todd, Matthew H.; Silva, Daniel Gedder; da Silva Emery, Flavio; Carlson, J. Eric; Zheng, Shao-Liang; Vleminckx, Margot; Matheeussen, An; Caljon, Guy; Pollastri, Michael P.; Sjö, Peter; Perry, Benjamin; Ferrins, Lori

doi:10.1021/acsinfecdis.3c00040

Cited by 3 publications

(5 citation statements)

References 22 publications

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“…Twenty-four compounds were donated by the Drugs for Neglected Diseases initiative (DND i ), for which the experimental data have been published. 21 An additional 36 compounds were contributed from Northeastern University, the experimental details for which may be found in a separate publication that has been recently published; 22 the compound identities are delineated in the Supporting Information - Biology , Tables S1 and S2.…”

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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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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“…1 H NMR (500 MHz, CDCl 3 ) δ 8.01 (d, J = 6.8 Hz, 1H), 7.57−7.39 (m, 3H), 7.25 (t, J = 7.9 Hz, 1H), 7.03 (ddd, J = 9.0, 6.7, 1.2 Hz, 1H), 6.84−6.74 (m, 1H), 6.69 (td, J = 6.8, 0.9 Hz, 1H), 3.99 (s, 1H), 3.79 (s, 3H), 3.66−3.56 (m, 4H), 3.04−2.89 (m, 2H), 2.44 (dd, J = 6.2, 4.8 Hz, 2H), 2.34 (s, 4H). 13 (10). 1 H NMR (500 MHz, CDCl 3 ) δ 8.09 (d, J = 6.8 Hz, 1H), 7.73−7.37 (m, 3H), 7.13 (ddd, J = 9.0, 6.7, 1.2 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.79 (td, J = 6.8, 1.0 Hz, 1H), 5.99 (s, 2H), 3.94 (s, 1H), 3.83−3.48 (m, 4H), 3.20−2.92 (m, 2H), 2.56 (dd, J = 6.3, 4.8 Hz, 2H), 2.47 (s, 4H).…”

Section: Methodsmentioning

confidence: 99%

“…The literature survey reveals the promising utility of a fused imidazo-pyridine scaffold for the discovery of new antileishmanial agents, and the active analogues demonstrate a diverse substitution tolerability at C2 and C3 positions as well as on the pyridine ring for the improved activity. Groebke–Blackburn–Bienaymé (GBB) multicomponent reaction (MCR) provides an easy access to construct a diverse set of imidazo-fused heterocycles in a single step utilizing different amidines, isonitriles, and aldehydes. − In order to identify new antileishmanial agents, a new GBB-MCR-based library has been evaluated against Leishmania amazonensis promastigotes and amastigotes, and physicochemical and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties have been examined with a view to predict important information about imidazo-pyridine analogues.…”

Section: Introductionmentioning

confidence: 99%

“…7 A C2-, C3-, and C7-trisubstituted imidazo-pyridine (3) has also demonstrated promising antileishmanial activity against L. major (IC 50 = 0.2 μM), 8 whereas another imidazo-pyridine-based compound (4) is found to be active against Trypanosoma cruzi amastigotes (IC 50 = 56.2 μM). 9 The literature survey reveals the promising utility of a fused imidazo-pyridine scaffold 10 for the discovery of new antileishmanial agents, and the active analogues demonstrate a diverse substitution tolerability at C2 and C3 positions as well as on the pyridine ring for the improved activity. Groebke− Blackburn−Bienaymé(GBB) multicomponent reaction (MCR) provides an easy access to construct a diverse set of imidazo-fused heterocycles in a single step utilizing different amidines, isonitriles, and aldehydes.…”

Section: Introductionmentioning

confidence: 99%

“…The literature survey reveals the promising utility of a fused imidazo-pyridine scaffold 10 for the discovery of new antileishmanial agents, and the active analogues demonstrate a diverse substitution tolerability at C2 and C3 positions as well as on the pyridine ring for the improved activity. Groebke–Blackburn–Bienaymé (GBB) multicomponent reaction (MCR) provides an easy access to construct a diverse set of imidazo-fused heterocycles in a single step utilizing different amidines, isonitriles, and aldehydes.…”

Section: Introductionmentioning

confidence: 99%

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Imidazo[1,2-a]pyrimidine as a New Antileishmanial Pharmacophore against Leishmania amazonensis Promastigotes and Amastigotes

Kumar,

Singh,

das Chagas Almeida

et al. 2023

ACS Omega

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Leishmania poses a substantial threat to the human population all over the globe because of its visceral and cutaneous spread engendered by all 20 species. Unfortunately, the available drugs against leishmania are already hobbled with toxicity, prolonged treatment, and increasing instances of acquirement of resistance. Under these grave circumstances, the development of new drugs has become imperative to keep these harmful microbes at bay. To this end, a Groebke−Blackburn−Bienaymémulticomponent reaction-based library of different imidazo-fused heterocycles has been synthesized and screened against Leishmania amazonensis promastigotes and amastigotes. Among the library compounds, the imidazo-pyrimidine 24 has been found to be the most effective (inhibitory concentration of 50% (IC 50 ) < 10 μM), with selective antileishmanial activity on amastigote forms, a stage of the parasite related to human disease. The compound 24 has exhibited an IC 50 value of 6.63 μM, being ∼two times more active than miltefosine, a reference drug. Furthermore, this compound is >10 times more destructive to the intracellular parasites than host cells. The observed in vitro antileishmanial activity along with suitable in silico physicochemical and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of compound 24 reinforce the imidazo-pyrimidine scaffold as a new antileishmanial pharmacophore and encourage further murine experimental leishmaniasis studies.

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Discovery of a Series of Macrocycles as Potent Inhibitors of Leishmania Infantum

Riu,

Ruppitsch,

Duy Vo

et al. 2024

J. Med. Chem.

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Macrocycles are prominent among drugs for treatment of infectious disease, with many originating from natural products. Herein we report on the discovery of a series of macrocycles structurally related to the natural product hymenocardine. Members of this series were found to inhibit the growth of Plasmodium falciparum, the parasite responsible for most malaria cases, and of four kinetoplastid parasites. Notably, macrocycles more potent than miltefosine, the only oral drug used for the treatment of the neglected tropical disease visceral leishmaniasis, were identified in a phenotypic screen of Leishmania infantum. In vitro profiling highlighted that potent inhibitors had satisfactory cell permeability with a low efflux ratio, indicating their potential for oral administration, but low solubility and metabolic stability. Analysis of predicted crystal structures suggests that optimization should focus on the reduction of π−π crystal packing interactions to reduce the strong crystalline interactions and improve the solubility of the most potent lead.

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Structure–Property Optimization of a Series of Imidazopyridines for Visceral Leishmaniasis

Cited by 3 publications

References 22 publications

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

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

Imidazo[1,2-a]pyrimidine as a New Antileishmanial Pharmacophore against Leishmania amazonensis Promastigotes and Amastigotes

Discovery of a Series of Macrocycles as Potent Inhibitors of Leishmania Infantum

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