Compound C21(Instituto Politécnico Nacional)

Angiotensin II AT2 receptor (AT2R) activation leads to significant anti-fibrotic and anti-inflammatory effects in diseased organs, which has led to clinical trial evaluation of the AT2R agonist, Compound 21 (C21), as a treatment for idiopathic pulmonary fibrosis (IPF). In this study, the anti-fibrotic effects of a more selective AT2R ligand, β-Pro7 angiotensin III (β-Pro7 Ang III), with >20,000-fold affinity for the AT2R over the AT1R, were compared with that of C21 or the currently used IPF medication, pirfenidone, in mice with bleomycin (BLM)-induced pulmonary fibrosis. Adult female BALB/c mice received a double intranasal instillation of BLM (20 mg/kg/day) seven days apart and were maintained until day 35, while control mice were instilled with saline (SAL) seven days apart and maintained for the same time period. Sub-groups of BLM-injured mice were then treated on day 28 with vehicle (SAL), C21 (0.3 mg/kg/day) or β-Pro7 Ang III (0.1 mg/kg/day) via seven-day subcutaneously implanted osmotic minipumps, or daily from days 28 to 35 via orally administered pirfenidone (100 mg/kg/day). At day-35 post-injury, measures of lung fibrosis and compliance were evaluated. Compared with their SAL-instilled counterparts, SAL-treated BLM-injured mice presented with a significantly increased lung Ashcroft score, Masson’s trichrome-stained and second harmonics generation-measured fibrosis, myofibroblast accumulation, and TGF-β1 expression, but reduced lung dynamic compliance at day-35 post-injury. While all treatments evaluated attenuated the BLM-induced lung myofibroblast accumulation and TGF-β1 expression, AT2R stimulation, but not pirfenidone, attenuated lung collagen deposition after seven days. β-Pro7 Ang III also significantly restored lung compliance and promoted collagen-degrading matrix metalloproteinase-2 activity. These findings highlighted the therapeutic value of selectively targeting the AT2R for treating IPF.

Chagas disease has an ineffective drug treatment despite efforts made over the last four decades. The carbonic anhydrase of Trypanosoma cruzi (α-TcCA) has emerged as an interesting target for the design of new antiparasitic compounds due to its crucial role in parasite processes.

The aim in this study was identify potential α-TcCA inhibitors with trypanocidal activity.

A maximum common substructure (MCS) and molecular docking were used to carried out a ligand- and structure-based virtual screening of ZINC20 and MolPort databases. The compounds selected were evaluated in an in vitro model against the NINOA strain of Trypanosoma cruzi, and cytotoxicity was determined in a murine model of macrophage cells J774.2.

Five sulfonamide derivatives (C7, C9, C14, C19, and C21) had the highest docking scores (-6.94 to -8.31 kcal/mol). They showed key residue interactions on the active site of the α-TcCA and good biopharmaceutical and pharmacokinetic properties. C7, C9, and C21 had half-maximal inhibitory concentration (IC50) values of 26, 61.6, and 49 μM, respectively, against NINOA strain epimastigotes of Trypanosoma cruzi.

Compounds C7, C9, and C21 showed trypanocidal activity; therefore, these results encourage the development of new trypanocidal agents based in their scaffold.