Palladium-mediated synthesis and biological evaluation of C-10b substituted Dihydropyrrolo[1,2-b]isoquinolines as antileishmanial agents

Barbolla, Iratxe; Hernández-Suárez, Leidi; Quevedo-Tumailli, Viviana; Nocedo-Mena, Deyani; Arrasate, Sonia; Dea-Ayuela, María Auxiliadora; González-Dı́az, Humberto; Sotomayor, Nuria; Lete, Esther

doi:10.1016/j.ejmech.2021.113458

Cited by 13 publications

(16 citation statements)

References 67 publications

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“…As mentioned in the introduction, the IFPTML algorithm is useful for finding predictive models for multiobjective optimization of compounds. In fact, we have already used IFPTML models for the study of new pyrroloisoquinolines vs different Leishmania species . However, all steps of IFPTML analysis needed to be performed on different software and/or using different manual operations.…”

Section: Resultsmentioning

confidence: 99%

“…The SOFT.PTML tool was used to pre-process a ChEMBL dataset of pre-clinical assays of antileishmanial compound candidates . This tool was also used to perform training/validation of alternative IFPTML models.…”

Section: Methodsmentioning

confidence: 99%

“…of assay and the need to obtain this information from many different data sources. We have recently reported the first PTML [(perturbation theory (PT) + machine learning (ML)] model that is capable of both explaining a very large dataset of preclinical assays of antileishmanial compounds and predicting the activity of new heterocycles (e.g., two series of pyrroloisoquinolines synthesized by our group) against different species of Leishmania . Nevertheless, the development process of this first PTML model and its subsequent use for the prediction of new antileishmanial hits were laborious.…”

Section: Introductionmentioning

confidence: 99%

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Prediction of Antileishmanial Compounds: General Model, Preparation, and Evaluation of 2-Acylpyrrole Derivatives

Santiago

Ortega-Tenezaca

Barbolla

et al. 2022

J. Chem. Inf. Model.

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In this work, the SOFT.PTML tool has been used to pre-process a ChEMBL dataset of pre-clinical assays of antileishmanial compound candidates. A comparative study of different ML algorithms, such as logistic regression (LOGR), support vector machine (SVM), and random forests (RF), has shown that the IFPTML-LOGR model presents excellent values of specificity and sensitivity (81–98%) in training and validation series. The use of this software has been illustrated with a practical case study focused on a series of 28 derivatives of 2-acylpyrroles 5a,b, obtained through a Pd(II)-catalyzed C–H radical acylation of pyrroles. Their in vitro leishmanicidal activity against visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis was evaluated finding that compounds 5bc (IC50 = 30.87 μM, SI > 10.17) and 5bd (IC50 = 16.87 μM, SI > 10.67) were approximately 6-fold more selective than the drug of reference (miltefosine) in in vitro assays against L. amazonensis promastigotes. In addition, most of the compounds showed low cytotoxicity, CC50 > 100 μg/mL in J774 cells. Interestingly, the IFPMTL-LOGR model predicts correctly the relative biological activity of these series of acylpyrroles. A computational high-throughput screening (cHTS) study of 2-acylpyrroles 5a,b has been performed calculating >20,700 activity scores vs a large space of 647 assays involving multiple Leishmania species, cell lines, and potential target proteins. Overall, the study demonstrates that the SOFT.PTML all-in-one strategy is useful to obtain IFPTML models in a friendly interface making the work easier and faster than before. The present work also points to 2-acylpyrroles as new lead compounds worthy of further optimization as antileishmanial hits.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prediction of Antileishmanial Compounds: General Model, Preparation, and Evaluation of 2-Acylpyrrole Derivatives

Santiago

Ortega-Tenezaca

Barbolla

et al. 2022

J. Chem. Inf. Model.

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“…Of these, nine research articles, ten reviews, and one editorial from 18 sources, the journal Current Topics in Medicinal Chemistry was the only one that submitted more than one document (three documents). Finally, all the documents found, after excluding the repeated ones, were as follows: [4,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. After reading the abstracts, the articles presented in Table 1 were selected.…”

Section: Wos Analysis (Web Of Science Core Collection)mentioning

confidence: 99%

Artificial intelligence and machine learning in Leishmania drug discovery

Diéguez-Santana

Mazón-Ortiz

Cerda-Mejía

et al. 2022

Proceedings of MOL2NET'22, Conference on Molecular, Biomedical &Amp; Computational Sciences and Engineering, 8th Ed. - MOL2NET:

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“…The scientific community has been deeply involved in the search for new drugs for HAT and leishmaniasis. − Different drug classes have been discovered, with aryl groups with hydroxy, methoxy, or alkyl substituents that decorate the fused aryl or heteroaryl nucleus, including quinolines. , Some hydrazone derivatives were also described as being active against Leishmania. In our drug development program, the pyrimido[5,4- d ]pyrimidine scaffold (Figure ) has been used to generate new biologically active compounds …”

mentioning

confidence: 99%

Pyrimido[5,4-d]pyrimidine-Based Compounds as a Novel Class of Antitrypanosomal and Antileishmanial Agents

Lopes

Cordeiro-da-Silva

Carvalho

2022

ACS Med. Chem. Lett.

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Sleeping sickness and leishmaniasis are neglected tropical diseases that threaten millions of people. The currently available therapies present several limitations, including high toxicity, lack of efficacy, and emerging drug resistance, prompting a search for novel therapeutic agents. In this work, we designed, synthesized, and in vitro evaluated the activity of new pyrimido[5,4-d]pyrimidines against Trypanosoma brucei and Leishmania infantum (promastigote and amastigote forms). The cytotoxicity of the compounds against the THP1 cell line was also assessed. Most tested compounds presented low micromolar activity against T. brucei with IC50 values in the range between 0.9 and 13.4 μM, and one compound also showed activity against L. infantum (IC50 = 3.13 μM). Several molecules presented a selectivity index higher than 10. The most active compound against booth parasites is derivative 4c, with IC50 = 0.94 μM (SI > 107) against T. brucei and IC50 = 3.13 μM (SI > 32) against L. infantum. This data enabled the identification of a new promising molecular scaffold for developing a novel class of antitrypanosomal and antileishmanial agents.

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Palladium-mediated synthesis and biological evaluation of C-10b substituted Dihydropyrrolo[1,2-b]isoquinolines as antileishmanial agents

Cited by 13 publications

References 67 publications

Prediction of Antileishmanial Compounds: General Model, Preparation, and Evaluation of 2-Acylpyrrole Derivatives

Prediction of Antileishmanial Compounds: General Model, Preparation, and Evaluation of 2-Acylpyrrole Derivatives

Artificial intelligence and machine learning in Leishmania drug discovery

Pyrimido[5,4-d]pyrimidine-Based Compounds as a Novel Class of Antitrypanosomal and Antileishmanial Agents

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