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

• Published in: Journal of chemical information and modeling Vol. 62; no. 16; pp. 3928 - 3940
• Main Authors: Santiago, Carlos, Ortega-Tenezaca, Bernabé, Barbolla, Iratxe, Fundora-Ortiz, Brenda, Arrasate, Sonia, Dea-Ayuela, María Auxiliadora, González-Díaz, Humberto, Sotomayor, Nuria, Lete, Esther
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22-08-2022
• Subjects: Acylation; Algorithms; Antiprotozoal Agents - pharmacology; Assaying; Biological activity; Cell Line; Comparative studies; Lead compounds; Leishmania; Optimization; Pharmaceutical Modeling; Pyrroles; Support vector machines; Toxicity
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.2c00731

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.