In the North of Brazil (Pará and Amazonas states) the leaves of the plant Talinum triangulare (popular: cariru) replace spinach as food. From a phytochemical point of view, they are rich in compounds of the group of pheophytins. These substances, related to chlorophyll, have photophysical properties that give them potential application in photodynamic therapy. Human serum albumin (HSA) is one of the main endogenous vehicles for biodistribution of molecules by blood plasma. Association constants and thermodynamic parameters for the interaction of HSA with pheophytin from Talinum triangulare were studied by UV-Vis absorption, fluorescence techniques, and molecular modeling (docking). Fluorescence quenching of the HSA’s internal fluorophore (tryptophan) at temperatures 296 K, 303 K, and 310 K, resulted in values for the association constants of the order of 10⁴ L∙mol⁻¹, indicating a moderate interaction between the compound and the albumin. The negative values of ΔG° indicate a spontaneous process; ΔH° = 15.5 kJ∙mol⁻¹ indicates an endothermic process of association and ΔS° = 0.145 kJ∙mol⁻¹∙K⁻¹ shows that the interaction between HSA and pheophytin occurs mainly by hydrophobic factors. The observed Trp fluorescence quenching is static: there is initial non-fluorescent association, in the ground state, HSA:Pheophytin. Possible solution obtained by a molecular docking study suggests that pheophytin is able to interact with HSA by means of hydrogen bonds with three lysine and one arginine residues, whereas the phytyl group is inserted in a hydrophobic pocket, close to Trp-214.

Clinical data acquired over the last decade on non-small cell lung cancer (NSCLC) treatment with small molecular weight Epidermal Growth Factor Receptor (EGFR) inhibitors have shown significant influence of EGFR point mutations and in-frame deletions on clinical efficacy. Identification of small molecules capable of inhibiting the clinically relevant EGFR mutant forms is desirable, and novel chemical scaffolds might provide knowledge regarding selectivity among EGFR forms and shed light on new strategies to overcome current clinical limitations. Design, synthesis, docking studies and in vitro evaluation of N-(3-(3-phenylureido)quinoxalin-6-yl) acrylamide derivatives (7a-m) against EGFR mutant forms are described. Compounds 7h and 7l were biochemically active in the nanomolar range against EGFR_wt and EGFR_L858R. Molecular docking and reaction enthalpy calculations have shown the influence of the combination of reversible and covalent binding modes with EGFR on the inhibitory activity. The inhibitory profile of 7h against a panel of patient-derived tumor cell lines was established, demonstrating selective growth inhibition of EGFR related cells at 10 μM among a panel of 30 cell lines derived from colon, melanoma, breast, bladder, kidney, prostate, pancreas and ovary tumors.

A series of 3-substituted-7-aminoalcoxy-coumarin was designed and evaluated as cholinesterase inhibitors and antioxidants. All compounds were effective in inhibiting AChE with potencies in the nanomolar range. The 3-(4-(dimethylamino)phenyl)-7-aminoethoxy-coumarin (6a) was considered a hit, showing good AChE inhibition potency (IC50 = 20 nM) and selectivity (IC50 BuChE/AChE = 354), quite similar to the reference drug donepezil (IC50 = 6 nM; IC50 BuChE/AChE = 365), also presenting antioxidant properties, low citotoxicity and good-predicted ADMET properties. The mode of action (mixed-type) and SAR analysis for this series of compounds were described by means of kinetic and molecular modeling evaluations.

Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N-acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able to revert the events associated with the progression of PAH in animal models. However, in spite of having a dual profile as PDE4 inhibitor and adenosine A_2A receptor agonist, LASSBio-1359 does not present balanced potencies in the modulation of these two targets, which difficult its therapeutic use. In this paper, we describe the design concept of LASSBio-1835, a novel structural analogue of LASSBio-1359, planned by exploiting ring bioisosterism. Using X-ray powder diffraction, calorimetric techniques, and molecular modeling, we clearly indicate the presence of a preferred synperiplanar conformation at the amide function, which is fixed by an intramolecular 1,5-N∙∙∙S σ-hole intramolecular interaction. Moreover, the evaluation of LASSBio-1835 (4) as a PDE4 inhibitor and as an A_2A agonist confirms it presents a more balanced dual profile, being considered a promising prototype for the treatment of PAH.