Functionalization of 2,4-Dichloropyrimidines by 2,2,6,6-Tetramethylpiperidyl Zinc Base Enables Modular Synthesis of Antimalarial Diaminopyrimidine P218 and Analogues

Meirelles, Matheus A.; Toledo, Ian de; Thurow, Samuel; Barreiro, Gabriela; Counago, R.M.; Pilli, Ronaldo A.

doi:10.1021/acs.joc.3c00500

Cited by 3 publications

(3 citation statements)

References 24 publications

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“…Pilli and co-workers have recently reported the use of TMP 2 Zn·2MgCl 2 ·2LiCl 2 in the synthesis of antimalarial P218 ( 52 ) via zincation of a dichloroalkoxypyrimidine precursor 50 in the only remaining heteroaryl C–H position before trapping with iodine (Scheme 13 ). 40 Notably, a high yield of 88% was obtained without reaction at the chloroaryl, enone, or ester moieties after a short optimisation.…”

Section: Csp 2 –H Functionalisation Using Zinc Basesmentioning

confidence: 99%

Zinc-Mediated C–H Metalations in Modern Organic Synthesis

Barker,

Wanic,

Melvin

2023

Synthesis

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C-H deprotometalations have long occupied a key role in modern organic synthesis in both the research laboratory and pharmaceutical and fine chemical manufacture, thanks to readily accessible reagents and well-established procedures. Typically, organolithiums are the reagent of choice thanks to high reactivity and ease of use but these are incompatible with base- and nucleophile-sensitive functional groups. In comparison, organozinc base complexes offer a milder approach to deprotonative C-H functionalisations, and compatibility with a wide range of functionalities which would be problematic when using the alternative organolithium or organomagnesium reagents has now been demonstrated. Here, we review the current state of the art in zinc-mediated C-H metalations at substituted arenes, heteroarenes and Csp3-H sites.

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Section: Csp 2 –H Functionalisation Using Zinc Basesmentioning

confidence: 99%

Zinc-Mediated C–H Metalations in Modern Organic Synthesis

Barker,

Wanic,

Melvin

2023

Synthesis

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“…However, this synthetic route also poses significant challenges due to the use of complex, expensive chemical reagents and extensive purification methods. 21 The disadvantages of both synthetic routes have raised concerns regarding the high cost of production. Therefore, a simple and robust synthetic route is required for producing P218 to serve as a medicine at low cost.…”

Section: Psp Synthesismentioning

confidence: 99%

“…This method is scalable, up to multigram scale, allowing access to key intermediate 5, which has been a bottleneck in previous methods. 21 The synthetic procedure allowed us to produce P218 and its metabolite P218-OH in ten and twelve steps, respectively. Moreover, our development of these synthetic procedures will be a foundation for further derivatization and optimization of antimalarial drugs and other antifolate agents.…”

Section: Psp Synthesismentioning

confidence: 99%

Development of a Practical Synthetic Method for Clinical Candidate 3-(2-{3-[(2,4-Diamino-6-ethylpyrimidin-5-yl)oxy]propoxy} phenyl)propanoic acid (P218) and Its Hydroxylated Metabolites

Srimongkolpithak,

Vorasin,

Phumjan

et al. 2023

Synthesis

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Abstract3-(2-{3-[(2,4-Diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid, known as P218, has demonstrated great potency and safety in preclinical and human studies. However, the previous synthetic methods for P218 gave low yields and required hazardous reagents and challenging procedures. In this study, we have successfully developed a decagram-scale synthetic route for P218 with practical and scalable methods for large-scale production. Furthermore, this is also a first report of a novel synthetic approach for P218-OH, a hydroxylated metabolite of P218, by modification of our discovery route. Our synthetic procedures for P218 and P218-OH are a significant advancement in drug development processes, including manufacturing processes and drug metabolism studies.

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Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

Andrade Meirelles,

Almeida,

Sullivan

et al. 2024

J. Med. Chem.

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Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.

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Functionalization of 2,4-Dichloropyrimidines by 2,2,6,6-Tetramethylpiperidyl Zinc Base Enables Modular Synthesis of Antimalarial Diaminopyrimidine P218 and Analogues

Cited by 3 publications

References 24 publications

Zinc-Mediated C–H Metalations in Modern Organic Synthesis

Zinc-Mediated C–H Metalations in Modern Organic Synthesis

Development of a Practical Synthetic Method for Clinical Candidate 3-(2-{3-[(2,4-Diamino-6-ethylpyrimidin-5-yl)oxy]propoxy} phenyl)propanoic acid (P218) and Its Hydroxylated Metabolites

Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

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