Leucine rich repeat kinase 2 (LRRK2) inhibitors based on indolinone scaffold: Potential pro-neurogenic agents

Salado, Irene G.; Zaldívar-Díez, Josefa; Sebastián-Pérez, Víctor; Li, Lingling; Geiger, Larissa; González, Silvia Bárbara Álvarez; Campillo, Nuria E.; Gil, Carmen; Morales, Aixa V.; Pérez, Daniel I.; Martı́nez, Ana

doi:10.1016/j.ejmech.2017.06.060

Cited by 27 publications

(27 citation statements)

References 50 publications

(38 reference statements)

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“…Figure 1 presents an outline of the experimental process followed in this work. The database is a compilation of 67 molecules formerly synthesized in our research group and tested in LRRK2 enzyme [19]. In this assay LRRK2 kinase activity was measured and the results expressed as the percentage of enzyme inhibition for every compound, as it is further discussed in the previous reference.…”

Section: Resultsmentioning

confidence: 99%

QSAR Modelling to Identify LRRK2 Inhibitors for Parkinson’s Disease

Sebastián-Pérez

Martínez

Gil

et al. 2019

Journal of Integrative Bioinformatics

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Parkinson’s disease is one of the most common neurodegenerative illnesses in older persons and the leucine-rich repeat kinase 2 (LRRK2) is an auspicious target for its pharmacological treatment. In this work, quantitative structure–activity relationship (QSAR) models for identification of putative inhibitors of LRRK2 protein are developed by using an in-house chemical library and several machine learning techniques. The methodology applied in this paper has two steps: first, alternative subsets of molecular descriptors useful for characterizing LRRK2 inhibitors are chosen by a multi-objective feature selection method; secondly, QSAR models are learned by using these subsets and three different strategies for supervised learning. The qualities of all these QSAR models are compared by classical metrics and the best models are discussed in statistical and physicochemical terms.

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Section: Resultsmentioning

confidence: 99%

QSAR Modelling to Identify LRRK2 Inhibitors for Parkinson’s Disease

Sebastián-Pérez

Martínez

Gil

et al. 2019

Journal of Integrative Bioinformatics

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“…13 C-NMR (DMSO- d 6 ) δ 163.21, 140.20, 132.01, 129.89, 128.20, 127.00, 121.77, 121.25, 118.42, 114.06, 110.44, 20.39. [ 16 ]…”

Section: Methodsmentioning

confidence: 99%

Effect of a =X-NH-Fragment, (X = C, N), on Z/E Isomerization and ON/OFF Functionality of Isatin Arylhydrazones, ((Arylamino)Methylene)Indolin-2-Ones and Their Anions

et al. 2020

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The subject of this work was the study of thermally and photochemically stimulated Z ↔ E isomerization and hydrazo ↔ azo tautomerism of Z- and E-isomers of isatin arylhydrazones and ((arylamino)methylene)indolin-2-ones and their anions. Using NMR, UV-Vis spectroscopy, kinetic measurements, and HPLC, we studied the relationship of structure, (Z- and E-isomers), of these compounds and hydrazo=azo tautomerism. The ON/OFF functionality of these compounds and their anions using light to stimulate switching between ON and OFF states was investigated. We pointed out the characterization of the effect of =N- and =CH- structural fragments and aryl structure on ON and OFF states of isatin arylhydrazones and ((arylamino)methylene)indolin-2-ones.

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“…However, the yield was similar to the previous conditions used. To study the influence of the morpholino moiety in the kinase inhibition and to confirm the relevance of this chemical fragment in the biological activity, the synthesis of N-(6flurobenzothiazol-2-yl)-benzamide derivatives (19)(20)(21)(22)(23) was proposed and executed following the methodologies described above (Scheme 2). The chemical structures of all the newly synthetized compounds were assigned unequivocally based in their analytical and spectroscopic data (see experimental section).…”

Section: Design and Synthesis Of New Compoundsmentioning

confidence: 99%

Benzothiazole-Based LRRK2 Inhibitors as Wnt Enhancers and Promoters of Oligodendrocytic Fate

et al. 2019

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Leucine Rich Repeat Kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for Parkinson's Disease (PD). However, despite the significant amount of research done in the last decade, the precise function of LRRK2 remains largely unknown. Moreover, the therapeutic potential of its inhibitors is in its infancy with the first clinical trial having just started. In the present work, the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was investigated. We designed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the Wnt/β-catenin signaling pathway. Furthermore, compounds 5 and 14 were able to promote neural progenitors proliferation and drive their differentiation towards neuronal and oligodendrocytic cell fates. These results suggest potential new avenues for the application of LRRK2 inhibitors in demyelinating diseases in which oligodendrocyte cell-death is one of the pathological features.

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Leucine rich repeat kinase 2 (LRRK2) inhibitors based on indolinone scaffold: Potential pro-neurogenic agents

Cited by 27 publications

References 50 publications

QSAR Modelling to Identify LRRK2 Inhibitors for Parkinson’s Disease

QSAR Modelling to Identify LRRK2 Inhibitors for Parkinson’s Disease

Effect of a =X-NH-Fragment, (X = C, N), on Z/E Isomerization and ON/OFF Functionality of Isatin Arylhydrazones, ((Arylamino)Methylene)Indolin-2-Ones and Their Anions

Benzothiazole-Based LRRK2 Inhibitors as Wnt Enhancers and Promoters of Oligodendrocytic Fate

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