Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β-<i>N</i>-acetylhexosaminidase Activity

Tropak, Michael B.; Zhang, Jianmin; Yonekawa, Sayuri; Rigat, Brigitte; Aulakh, Virender S.; Smith, Matthew R.; Hwang, Hee-Jong; Ciufolini, Marco A.; Mahuran, Don J.

doi:10.1021/jm5017895

Cited by 9 publications

(5 citation statements)

References 31 publications

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“…Pyrimethamine (PMA; see Scheme a) is a dihydrofolate reductase (DHFR) inhibitor with widespread application in the therapy of some diseases caused by parasitic protozoa, namely, malaria − and toxoplasmosis. , Like most DHFR inhibitors, pyrimethamine has a 2,4-diaminopyrimidine scaffold ,,, that plays a key role in its biological activity. It is also the key molecular feature for intermolecular recognition in the solid state, with two hydrogen-bond donor sites and two acceptor sites.…”

Section: Introductionmentioning

confidence: 99%

Polymorphic Cocrystals of the Antimalarial Drug Pyrimethamine: Two Case Studies

Baptista

Castro

Rosado

et al. 2021

Crystal Growth & Design

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Polymorphism is known to have significant implications in the pharmaceutical industry. However, there are relatively few studies of polymorphic pharmaceutical cocrystals, and contributions to the systematic assessment, structural, and thermodynamic characterization of cocrystal polymorphs are of great relevance. This work reports cocrystal formation between pyrimethamine, a multifunctional API with a 2,4-diaminopyrimidine scaffold, common to many dihydrofolate reductase inhibitors, and two structurally related coformers, caffeine and theophylline, differing in their hydrogen-bonding donor ability. Two (1:1) enantiotropic cocrystal polymorphs were identified for both pyrimethamine:caffeine and pyrimethamine:theophylline. The contribution of differential scanning calorimetry to guide the cocrystal polymorphs discovery should be emphasized. The different hydrogen-bonding abilities of the coformers have consequences for the crystalline structures obtained. The crystalline structure of pyrimethamine:theophylline polymorph II, previously solved by Delori et al., is determined by the N PMA •••H−N THEO bond. Both pyrimethamine:caffeine polymorphs, whose crystalline structures were solved in this work, although differing in packing and synthon, share a common 2,4-diaminopyrimidine hydrogen-bonded chain pattern which has quite close similarity with pyrimethamine polymorph I. A similar infrared pattern in the N−H stretching region is observed for these three solid forms, and also for pyrimethamine:theophylline, polymorph I, which may anticipate a similar arrangement in this polymorph.

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Section: Introductionmentioning

confidence: 99%

Polymorphic Cocrystals of the Antimalarial Drug Pyrimethamine: Two Case Studies

Baptista

Castro

Rosado

et al. 2021

Crystal Growth & Design

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“…It was further tested more recently and gave a temporary improvement in measured enzyme activity, with one of four patients remaining stable while the other three continued to deteriorate. Seven years after the initial drug screening, more active forms of pyrimethamine were being sought, with the hope of finding a treatment for this deadly disease.…”

Section: Repurposing As a Path To New Drugsmentioning

confidence: 99%

Repurposing approved drugs on the pathway to novel therapies

Schein

2019

Medicinal Research Reviews

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The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

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“…After “rescued” proteins reach the low-pH environment of the lysosome, they dissociate from the chaperone molecule and are able to restore some level of enzyme activity. 63 One study in GM2 fibroblasts found that chaperone therapy is effective in increasing enzyme activity, but concluded that it should be combined with SRT for synergistic effects. 62 To date, efficacy of chaperone therapy in GM2 patients has not been confirmed, though fine-tuning of dose and delivery routes may prove beneficial.…”

Section: Therapy Developmentmentioning

confidence: 99%

Animal models of GM2 gangliosidosis: utility and limitations

Lawson¹,

Martin

2016

TACG

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GM2 gangliosidosis, a subset of lysosomal storage disorders, is caused by a deficiency of the glycohydrolase, β-N-acetylhexosaminidase, and includes the closely related Tay–Sachs and Sandhoff diseases. The enzyme deficiency prevents the normal, stepwise degradation of ganglioside, which accumulates unchecked within the cellular lysosome, particularly in neurons. As a result, individuals with GM2 gangliosidosis experience progressive neurological diseases including motor deficits, progressive weakness and hypotonia, decreased responsiveness, vision deterioration, and seizures. Mice and cats are well-established animal models for Sandhoff disease, whereas Jacob sheep are the only known laboratory animal model of Tay–Sachs disease to exhibit clinical symptoms. Since the human diseases are relatively rare, animal models are indispensable tools for further study of pathogenesis and for development of potential treatments. Though no effective treatments for gangliosidoses currently exist, animal models have been used to test promising experimental therapies. Herein, the utility and limitations of gangliosidosis animal models and how they have contributed to the development of potential new treatments are described.

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Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β-N-acetylhexosaminidase Activity

Cited by 9 publications

References 31 publications

Polymorphic Cocrystals of the Antimalarial Drug Pyrimethamine: Two Case Studies

Polymorphic Cocrystals of the Antimalarial Drug Pyrimethamine: Two Case Studies

Repurposing approved drugs on the pathway to novel therapies

Animal models of GM2 gangliosidosis: utility and limitations

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