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A series of seven chalcone-thiosemicarbazones (5a−5g) were synthesized and evaluated as potential new drugs (anti-leishmanial effect). Although four of the chalcone-thiosemicarbazones are already known, none of them or any compound in this class has been previously investigated for their effects on parasites of the Leishmania genus. The compounds were prepared in satisfactory yields (40−75%) and these compounds were evaluated against promastigotes, axenic amastigotes and intracellular amastigotes of L. amazonensis after 48 h of culture. The half maximal inhibitory concentration (IC50) values of the intracellular amastigotes were determined to be in the range of 3.40 to 5.95 µM for all compounds assayed. The selectivity index showed value of 15.05 for 5a, whereas pentamidine (reference drug) was more toxic in our model (SI = 2.32). Furthermore, to understand the preliminary relationship between the anti-leishmanial activity of the chalcone-thiosemicarbazones, their electronic (σ), steric (MR) and lipophilicity (π) properties were correlated, and the results indicated that moieties with electronic withdrawing effects increase the anti-leishmanial activity. The preliminary pharmacokinetic evaluation of one of the most active compound (5e) was studied via interaction to human serum albumin (HSA) using multiple spectroscopic techniques combined with molecular docking. The results of antiparasitic effects against L. amazonensis revealed the chalcone-thiosemicarbazone class to be novel prototypes for drug development against leishmaniasis.

The interaction between the main carrier of endogenous and exogenous compounds in the human bloodstream (human serum albumin, HSA) and a potential anticancer compound (the capsaicin analogue RPF101) was investigated by spectroscopic techniques (circular dichroism, steady-state, time-resolved, and synchronous fluorescence), zeta potential, and computational method (molecular docking). Steady-state and time-resolved fluorescence experiments indicated an association in the ground state between HSA:RPF101. The interaction is moderate, spontaneous (ΔG° < 0), and entropically driven (ΔS° = 0.573 ± 0.069 kJ/molK). This association does not perturb significantly the potential surface of the protein, as well as the secondary structure of the albumin and the microenvironment around tyrosine and tryptophan residues. Competitive binding studies indicated Sudlow’s site I as the main protein pocket and molecular docking results suggested hydrogen bonding and hydrophobic interactions as the main binding forces.