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.

中文翻译：

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抗利什曼原虫化合物的预测：2-酰基吡咯衍生物的一般模型、制备和评价

在这项工作中，SOFT.PTML 工具已用于预处理 ChEMBL 数据集，该数据集包含抗利什曼氏化合物候选物的临床前分析。对逻辑回归 (LOGR)、支持向量机 (SVM) 和随机森林 (RF) 等不同 ML 算法的比较研究表明，IFPTML-LOGR 模型具有出色的特异性和敏感性值 (81–98%) ) 在培训和验证系列中。该软件的使用已通过一个实际案例研究进行了说明，重点是通过 Pd(II) 催化的吡咯 C-H 自由基酰化获得的一系列 2-酰基吡咯5a和b的 28 种衍生物。它们对内脏( L. donovani ) 和皮肤 ( L. amazonensis)的体外杀利什曼原虫活性) 对利什曼病进行了评估，发现化合物5bc（IC ₅₀ = 30.87 μM，SI > 10.17）和5bd（IC _{50 = 16.87 μM，SI > 10.67）在}体外比参考药物（米替福新）的选择性高约 6 倍针对L. amazonensis前鞭毛体的测定。此外，大多数化合物在 J774 细胞中表现出低细胞毒性，CC ₅₀ > 100 μg/mL。有趣的是，IFPMTL-LOGR 模型正确预测了这些系列酰基吡咯的相对生物活性。已对 2-酰基吡咯5a、 b进行计算性高通量筛选 (cHTS) 研究，计算出 >20,700 的活动分数与涉及多个利什曼原虫物种、细胞系和潜在靶蛋白的 647 项测定的大空间相比。总体而言，该研究表明，SOFT.PTML 一体式策略有助于在友好的界面中获取 IFPTML 模型，从而使工作比以前更容易、更快。目前的工作还指出 2-酰基吡咯作为新的先导化合物值得进一步优化作为 antileishmanial 命中。