- Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis
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There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.
- Thomas, Michael,Brand, Stephen,De Rycker, Manu,Zuccotto, Fabio,Lukac, Iva,Dodd, Peter G.,Ko, Eun-Jung,Manthri, Sujatha,McGonagle, Kate,Osuna-Cabello, Maria,Riley, Jennifer,Pont, Caterina,Simeons, Frederick,Stojanovski, Laste,Thomas, John,Thompson, Stephen,Viayna, Elisabet,Fiandor, Jose M.,Martin, Julio,Wyatt, Paul G.,Miles, Timothy J.,Read, Kevin D.,Marco, Maria,Gilbert, Ian H.
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supporting information
p. 5905 - 5930
(2021/06/01)
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- Activating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels-Alder Reactions
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Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and only reactions under drastic conditions have previously been reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines, can be exceptionally activated by trifluoroacetylation. This allows a Diels-Alder cycloaddition under very mild reaction conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general and scalable and has an excellent functional group tolerance. A straightforward synthesis of a key intermediate of Bayer's Vericiguat illustrates the potential of this cycloaddition strategy. Quantum mechanical calculations show how the simple N-trifluoroacetylation of 2-hydrazonylpyrimidines distorts the substrate into a transition-state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition.
- Le Fouler, Vincent,Chen, Yu,Gandon, Vincent,Bizet, Vincent,Salomé, Christophe,Fessard, Thomas,Liu, Fang,Houk,Blanchard, Nicolas
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supporting information
p. 15901 - 15909
(2019/10/22)
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- Synthesis, characterization and pharmacological study of 4,5-dihydropyrazolines carrying pyrimidine moiety
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A series of 5-bromo-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)pyrimidine were prepared under conventional heating as well as microwave reaction condition. The newly synthesized compounds were characterized on the basis of elemental, spectral and single crystal X-ray studies. These new compounds were screened for their antioxidant, anti-inflammatory and analgesic activities. Some of these compounds exhibited potent biological activities compared to the standard drug.
- Adhikari, Adithya,Kalluraya, Balakrishna,Sujith, Kizhakke Veedu,Gouthamchandra, Kuluvar,Jairam, Ravikumar,Mahmood, Riaz,Sankolli, Ravish
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p. 467 - 474
(2012/11/07)
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- Synthesis of [1,2,4]-triazolo[1,5-a]pyrimidines by Dimroth rearrangement of [1,2,4]-triazolo[4,3-a]pyrimidines: A theoretical and NMR study
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Novel [1,2,4]-triazolo-[1,5-a]pyrimidine derivatives were prepared by oxidative cyclization of suitable N-benzylidene-N′-pyrimidin-2-yl hydrazine precursors, followed by a Dimroth rearrangement. Reaction of 6-bromo-[1,2,4]-triazolo-[4,3-a]pyrimidines with
- Salgado, Antonio,Varela, Carmen,García Collazo, Ana María,García, Fernando,Pevarello, Paolo,Alkorta, Ibon,Elguero, José
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experimental part
p. 13 - 24
(2011/04/14)
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- Substituted Triazolo-Pyrimidine Compounds
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The present invention relates to substituted triazolo-pyrimidine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted triazolo-pyrimidine compounds and methods of t
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Page/Page column 12
(2011/07/08)
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