Compound 14(University of Coimbra)

Based on the biological relevance of synthetic dipolar heterocyclics, fourteen mesoionic compounds, that is, 4‐phenyl‐5‐(4’ or 3’ or 2’,4’‐R‐styryl)‐1,3,4‐thiadiazolium‐2‐phenylamine chlorides (R = H ( 1 ), 4’‐F ( 2 ), 4’‐Cl ( 3 ), 4’‐Br ( 4 ), 3’‐Cl ( 5 ), 3’‐Br ( 6 ), 2’,4’‐diF ( 7 ), 2’,4’‐diCl ( 8 ), 4’‐OH ( 9 ), 2’‐OMe ( 10 ), 4’‐OEt ( 11 ), 4’‐Me ( 12 ), 4’‐OMe ( 13 ), and 4’‐NO 2 ( 14 )) were in silico evaluated to suggest their potential antitumoral profile, being validated by in vitro and in vivo assays against a mammary adenocarcinoma (Ehrlich tumor) and an undifferentiated mesenchymal sarcoma (S180 tumor). The compounds that had potency lower than 20 µM were those with the experimental hydrophobicity (log k w ) in the range of 3.90 – 4.47, e.g., mesoionic compound containing nitro‐moiety ( 14 , IC 50 = 7.78 ± 0.06 µM) was identified as the leading compound to inhibit Ehrlich tumor proliferation, following the best docking score values obtained to KIT kinase domain and inducible nitric oxide synthase. In contrast, the mesoionic compound with hydroxy‐moiety ( 9 , IC 50 = 5.92 ± 0.67 µM) in the styryl aromatic ring was the most active in S180 tumour cells. The synergism of the natural flavonoid Quercetin with 14 and 9 was in vivo evaluated, opening new avenues to antitumoral treatment.