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Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3?.

ABSTRACT: Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3?, allow the systematic synthesis of related fragment analogues to explore fragment-level structure-activity relationship, and finally lead to the synthesis of a more potent compound.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5018862 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β.

Wang Yikai Y Wach Jean-Yves JY Sheehan Patrick P Zhong Cheng C Zhan Chenyang C Harris Richard R Almo Steven C SC Bishop Joshua J Haggarty Stephen J SJ Ramek Alexander A Berry Kayla N KN O'Herin Conor C Koehler Angela N AN Hung Alvin W AW Young Damian W DW

ACS medicinal chemistry letters 20160714 9

Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow the systematic synthesis of related fragment analogues to explore fragment-level structure-activity relationship, and finally lead to the synthesis of a more potent compound. ...[more]

PMID: 27660690

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Project description:BackgroundMalaria remains the world's most important devastating parasitic disease. Of the five species of Plasmodium known to infect and cause human malaria, Plasmodium falciparum is the most virulent and responsible for majority of the deaths caused by this disease. Mainstream drug therapy targets the asexual blood stage of the malaria parasite, as the disease symptoms are mainly associated with this stage. The prevalence of malaria parasite strains resistance to existing anti-malarial drugs has made the control of malaria even more challenging and hence the development of a new class of drugs is inevitable.MethodsScreening against different drug resistant and sensitive strains of P. falciparum was performed for few bicyclic lactam-based motifs, exhibiting a broad spectrum of activity with low toxicity generated via a focussed library obtained from diversity oriented synthesis (DOS). The synthesis and screening was followed by an in vitro assessment of the possible cytotoxic effect of this class of compounds on malaria parasite.ResultsThe central scaffold a chiral bicyclic lactam (A) and (A') which were synthesized from (R)-phenylalaninol, levulinic acid and 3-(2-nitrophenyl) levulinic acid respectively. The DOS library was generated from A and from A', by either direct substitution with o-nitrobenzylbromide at the carbon α- to the amide functionality or by conversion to fused pyrroloquinolines. Upon screening this diverse library for their anti-malarial activity, a dinitro/diamine substituted bicyclic lactam was found to demonstrate exceptional activity of >85% inhibition at 50 μM concentration across different strains of P. falciparum with no toxicity against mammalian cells. Also, loss of mitochondrial membrane potential, mitochondrial functionality and apoptosis was observed in parasite treated with diamine-substituted bicyclic lactams.ConclusionsThis study unveils a DOS-mediated exploration of small molecules with novel structural motifs that culminates in identifying a potential lead molecule against malaria. In vitro investigations further reveal their cytocidal effect on malaria parasite growth. It is not the first time that DOS has been used as a strategy to identify therapeutic leads against malaria, but this study establishes the direct implications of DOS in scouting novel motifs with anti-malarial activity.

Dataset Information

Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3?.

Publications

Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β.

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