Synthesis, anti-trypanosoma brucei evaluation and structure-activity relationship of novel N4- aryl thiosemicarbazones derived from 1-indanones

O. FUSCO; M. C. SORAIRES SANTACRUZ; L. M. FINKIELSZTEIN; E. BONTEMPI

La Plata

Workshop; International Workshop on drug design and neglected tropical diseases; 2016

The neglected disease human African trypanosomiasis is a fatal parasitic infection caused by the protozoan Trypanosoma brucei. There is no effective vaccine and the current available drugs for the treatment suffer from serious drawbacks: low efficacy, severe toxic side effects, and drug resistance. This situation underlines the urgent need for the development of new drugs. In this regard, thiosemicarbazones and their derivatives have presented multiple biological properties and in particular anti-trypanosomal activities. To discover new compounds that show effectiveness against T. brucei our research group synthesized a series of N4-aryl thiosemicarbazones derived from 1-indanones (N4-TSCs), evaluated their trypanocidal activity in the bloodstream form of T. brucei brucei strain 90-13 and studied the structure-activity relationship.Twelve N4-TSCs were synthesized by two different synthetic methods. Comparatives analysis of percentage yields and total reaction time for all compounds by both conventional and microwave-assisted method was carried out. The results suggest that using microwave irradiation leads to higher yields within very short reaction times. Among all tested compounds against T. brucei, compound 2 was found to be the most active. In addition, compounds 4 and 8 also exhibited excellent activity. Eleven compounds out of twelve showed better IC50 values than the reference drug eflornithine (IC 50=21.6±2.29 µM).Structure-activity relationship revealed that the nature of the substituent in the N4-phenyl group has an important effect: compounds with nitro group were the most active. The presence of electron­donating substituents in R3 reduce markedly the anti-T. brucei activity in both series. Moreover, 5,6-dimethoxy substitution in the indanic ring improves the activity against the parasite.These synthesized compounds may contribute to the treatment of trypanosomiasis. Further studies (QSAR= quantitative structure-activity and pharmacophore search) could explain the influence of the type and position of the substituents in the observed anti-trypanosomal action.