Virtual and in Vitro Screening Employing a Repurposing Approach Reveal 13-cis-Retinoic Acid is a PTP1B Inhibitor.

Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti-diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options, as approved drugs targeting different pharmacological objectives are still unavailable. One potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway.

3-Benzylaminomethyl Lithocholic Acid Derivatives Exhibited Potent and Selective Uncompetitive Inhibitory Activity Against Protein Tyrosine Phosphatase 1B (PTP1B).

Protein tyrosine phosphatase 1B (PTP1B) is a promising drug target for treating type 2 diabetes (T2DM) and obesity. As a result, developing new therapies that target PTP1B is an attractive strategy for treating these diseases. Herein, we detail the synthesis of 15 lithocholic acid (LA) derivatives, each containing different benzylaminomethyl groups attached to the C3 position of the steroid skeleton.

Similarity searching for anticandidal agents employing a repurposing approach.

Fungal infections caused by Candida are still a public health concern. Particularly, the resistance to traditional chemotherapeutic agents is a major issue that requires efforts to develop new therapies. One of the most interesting approaches to finding new active compounds is drug repurposing aided by computational methods.

Anti-Diabetic Activity of Glycyrrhetinic Acid Derivatives FC-114 and FC-122: Scale-Up, In Silico, In Vitro, and In Vivo Studies.

Type 2 diabetes (T2D) is one of the most common diseases and the 8th leading cause of death worldwide. Individuals with T2D are at risk for several health complications that reduce their life expectancy and quality of life. Although several drugs for treating T2D are currently available, many of them have reported side effects ranging from mild to severe.

Exploring the fuzzy border between senolytics and senomorphics with chemoinformatics and systems pharmacology.

Senescent cells accumulate within tissues during aging and secrete an array of pro-inflammatory molecules known as senescent-associated secretory phenotype (SASP), which contribute to the appearance and progression of various chronic degenerative diseases. Novel pharmacological approaches aimed at modulating or eliminating senescent cells´ harmful effects have recently emerged: Senolytics are molecules that selectively eliminate senescent cells, while senomorphics modulate or decrease the inflammatory response to specific SASP. So far, the physicochemical, structural, and pharmacological properties that define these two kinds of pharmacological approaches remain unclear.

Synthesis and Cytotoxic Activity of Combretastatin A-4 and 2,3-Diphenyl-2-indazole Hybrids.

Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious problem, and the development of new active compounds remains a constant need.

Indole- and Pyrazole-Glycyrrhetinic Acid Derivatives as PTP1B Inhibitors: Synthesis, In Vitro and In Silico Studies.

Regulating insulin and leptin levels using a protein tyrosine phosphatase 1B (PTP1B) inhibitor is an attractive strategy to treat diabetes and obesity. Glycyrrhetinic acid (GA), a triterpenoid, may weakly inhibit this enzyme. Nonetheless, semisynthetic derivatives of GA have not been developed as PTP1B inhibitors to date.

Synthesis, Antiprotozoal Activity, and Cheminformatic Analysis of 2-Phenyl-2-Indazole Derivatives.

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported.

Design, Synthesis and Anticandidal Evaluation of Indazole and Pyrazole Derivatives.

Candidiasis, caused by yeasts of the genus Candida, is the second cause of superficial and mucosal infections and the fourth cause of bloodstream infections. Although some antifungal drugs to treat candidiasis are available, resistant strains to current therapies are emerging. Therefore, the search for new candicidal compounds is certainly a priority.

The giardicidal activity of lobendazole, fabomotizole, tenatoprazole and ipriflavone: A ligand-based virtual screening and in vitro study.

A ligand-based virtual screening study to search for giardicidal compounds on a 6551 ChEMBL drugs database was carried out using molecular similarity. Three fingerprints implemented in MayaChemTools with different design and validated by ROC curves, were used. Twelve compounds were retrieved from this screening, from which, four representative compounds were selected to carry out biological assays.

Synthesis and Biological Evaluation of 2H-Indazole Derivatives: Towards Antimicrobial and Anti-Inflammatory Dual Agents.

Indazole is considered a very important scaffold in medicinal chemistry. It is commonly found in compounds with diverse biological activities, e.g.

Benzoic Acid Derivatives with Trypanocidal Activity: Enzymatic Analysis and Molecular Docking Studies toward Trans-Sialidase.

Chagas, or American trypanosomiasis, remains an important public health problem in developing countries. In the last decade, -sialidase has become a pharmacological target for new anti-Chagas drugs. In this work, the aims were to design and find a new series of benzoic acid derivatives as -sialidase (TS) inhibitors and anti-trypanosomal agents.

Synthesis of Curcuminoids and Evaluation of Their Cytotoxic and Antioxidant Properties.

Curcumin () and ten derivatives (-) were synthesized and evaluated as cytotoxic and antioxidant agents. The results of primary screening by Sulforhodamine B assay against five human cancer cell lines (U-251 MG, glioblastoma; PC-3, human prostatic; HCT-15, human colorectal; K562, human chronic myelogenous leukemia; and SKLU-1, non-small cell lung cancer) allowed us to calculate the half maximal inhibitory concentration (IC) values for the more active compounds against HCT-15 and K562 cell lines. Compounds and were the most active against both cell lines and were more active than curcumin itself.

Activity cliffs and activity cliff generators based on chemotype-related activity landscapes.

Activity cliffs have large impact in drug discovery; therefore, their detection and quantification are of major importance. This work introduces the metric activity cliff enrichment factor and expands the previously reported activity cliff generator concept by adding chemotype information to representations of the activity landscape. To exemplify these concepts, three molecular databases with multiple biological activities were characterized.

Chemoinformatic characterization of activity and selectivity switches of antiprotozoal compounds.

Background: Benzimidazole derivatives are promising compounds for the treatment of parasitic infections. The structure-activity relationships of 91 benzimidazoles with activity against Trichomonas vaginalis and Giardia intestinalis were analyzed using a novel activity landscape modeling approach.

Results: We identified two prominent cases of 'activity switches' and 'selectivity switches' where two R group substitutions in the benzimidazole scaffold completely invert the activity and selectivity pattern for T.

Cyclic Systems Distribution Along Similarity Measures: Insights for an Application to Activity Landscape Modeling.

The emerging concept of the activity landscape has been widely applied for structureactivity relationships (SAR) characterization. Since chemical space representation plays a crucial role in activity landscape modeling, an adequate selection of similarity measures is desirable. Herein a set of 658 cyclooxygenase inhibitors were structurally analyzed using 12 molecular similarity representations and two levels of chemotype classification.

Identifying Activity Cliff Generators of PPAR Ligands Using SAS Maps.

Structure-activity relationships (SAR) of compound databases play a key role in hit identification and lead optimization. In particular, activity cliffs, defined as a pair of structurally similar molecules that present large changes in potency, provide valuable SAR information. Herein, we introduce the concept of activity cliff generator, defined as a molecular structure that has a high probability to form activity cliffs with molecules tested in the same biological assay.

CASE plots for the chemotype-based activity and selectivity analysis: a CASE study of cyclooxygenase inhibitors.

Structure-activity characterization of molecular databases plays a central role in drug discovery. However, the characterization of large databases containing structurally diverse molecules with several end-points represents a major challenge. For this purpose, the use of chemoinformatic methods plays an important role to elucidate structure-activity relationships.

Activity landscape modeling of PPAR ligands with dual-activity difference maps.

Activation of peroxisome proliferator-activated receptor (PPAR) subtypes offers a promising strategy for the treatment of diabetes mellitus and metabolic diseases. Selective and dual PPAR agonists have been developed and the systematic characterization of their structure-activity relationships (SAR) is of major significance. Herein, we report a systematic description of the SAR of 168 compounds screened against the three PPAR subtypes using the principles of activity landscape modeling.

In vitro and in vivo trypanocidal activity of some benzimidazole derivatives against two strains of Trypanosoma cruzi.

The trypanocidal effect of five benzimidazole derivatives (1-5) was determined in vitro and in vivo assays against two strains of Trypanosoma cruzi (NINOA and INC5). The in vitro trypanocidal activity was evaluated by measuring the percentage of lysis of bloodstream trypomastigotes of T. cruzi.

Antiprotozoal activity of proton-pump inhibitors.

Parasitic diseases are still a major health problem in developing countries. In our effort to find new antiparasitic agents, in this Letter we report the in vitro antiprotozoal activity of omeprazole, lansoprazole, rabeprazole and pantoprazole against Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Molecular modeling studies were an important tool to highlight the potential antiprotozoal activity of these drugs.

Multitarget structure-activity relationships characterized by activity-difference maps and consensus similarity measure.

Dual and triple activity-difference (DAD/TAD) maps are tools for the systematic characterization of structure-activity relationships (SAR) of compound data sets screened against two or three targets. DAD and TAD maps are two- and three- dimensional representations of the pairwise activity differences of compound data sets, respectively. Adding pairwise structural similarity information into these maps readily reveals activity cliff regions in the SAR for one, two, or three targets.

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of some benzimidazole derivatives with trichomonicidal activity.

Trichomonosis is a common sexually transmitted infectious disease linked to reproductive health complications. Recently, the benzimidazole nucleus has emerged as a promising scaffold to develop new trichomonicidal agents. Despite the fact that large amounts of experimental data have been accumulated over the past eight years, no quantitative studies have yet been reported on this class of compounds.