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

Abstract

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.

Easy one-pot synthesis of multifunctionalized indole–pyrrole hybrids as a new class of antileishmanial agents

“…15 N-Pyridinyl-2-acyl pyrrole 11, reported in an interesting study by Santiago et al, showed activity against L. amazonensis and L. donovani promastigotes with IC 50 of 16.9 mM and 7.8 mM, respectively. 16 The last example of a pyrrolecontaining antileishmanial agent is compound 12 that showed IC 50 = 0.33 mg mL −1 (1.2 mM) against L. major promastigotes. 17 Among several strategies for the discovery of new hit and/or lead compounds, molecular hybridization has proven to be a good option.…”

Highly Accurate and Explainable Predictions of Small-Molecule Antioxidants for Eight In Vitro Assays Simultaneously through an Alternating Multitask Learning Strategy

“…In light of the observed correlations among data derived from various antioxidant activity assays, the adoption of a multitask learning strategy has the potential to enhance the predictive capabilities of the model. Multitask models for quantitative structure–biological effect relationships (mtk-QSBER) have been used to simultaneously predict activity, toxicity, and ADME end points across a range of biological targets and assay protocols. − For instance, these models have been used to identify new lead compounds with antileishmanial properties, design chemicals with dual pan-antiviral and anticytokine storm profiles, and discover multistrain inhibitors for antituberculosis therapy. − The mtk-QSBER models provide new perspectives and tools for drug design and biological effect prediction.…”