4 research outputs found
Synthesis and biological evaluation of new 3(2H)-pyridazinone derivatives as non-toxic anti-proliferative compounds against human colon carcinoma HCT116 cells
Novel 3(2H)-pyridazinone derivatives were designed, synthesised in
satisfactory yields and evaluated in different experimental assays to
assess their preliminary toxicity in vivo and anti-proliferative effects
against HCT116 cell lines in vitro. Artemia salina lethality test
provided LC50 values >100 mu g/mL for all compounds. Successive assays
revealed that some compounds were endowed with a promising
anti-proliferative effect against HCT116 cells, alone or stimulated by
serotonin as a pro-inflammatory factor in order to mimick an inflamed
model in vivo of cancer cell microenvironment. Moreover, the kinurenic
acid level after treatment with these newly synthesised compounds was
monitored as a marker of anti-proliferation in colon carcinoma models.
The IC50 values obtained for the best-in-class compounds were comparable
to that of daunorubicin as a reference drug. Conversely, these compounds
were not able to counteract the spontaneous migration of human cancer
HCT116 cell line in the wound healing paradigm
Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors
Twelve pyridazinones (T1-T12) containing the (2-fluorophenyl) piperazine
moiety were designed, synthesized, and evaluated for monoamine oxidase
(MAO) -A and -B inhibitory activities. T6 was found to be the most
potent MAO-B inhibitor with an IC50 value of 0.013 mu M, followed by T3
(IC50 = 0.039 mu M). Inhibitory potency for MAO-B was more enhanced by
meta bromo substitution (T6) than by para bromo substitution (T7). For
para substitution, inhibitory potencies for MAO-B were as follows: -Cl
(T3) > -N(CH3)(2) (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) >
-H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57
and 4.19 mu M and had the highest selectivity indices (SIs) for MAO-B
(120.8 and 107.4, respectively). T3 and T6 were found to be reversible
and competitive inhibitors of MAO-B with K-i values of 0.014 and 0.0071,
respectively. Moreover, T6 was less toxic to healthy fibroblast cells
(L929) than T3. Molecular docking simulations with MAO binding sites
returned higher docking scores for T6 and T3 with MAO-B than with MAO-A.
These results suggest that T3 and T6 are selective, reversible, and
competitive inhibitors of MAO-B and should be considered lead candidates
for the treatment of neurodegenerative disorders like Alzheimer's
disease