Promising Hybrids Derived from S-Allylcysteine and NSAIDs Fragments against Colorectal Cancer: Synthesis, In-vitro Evaluation, Drug-Likeness and In-silico ADME/tox Studies.

We synthesized twelve hybrids, S-allyl Cysteine methyl, ethyl and propyl ester-based non-steroidal anti-inflammatory drugs and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of all compounds was evaluated against SW480 human colon adenocarcinoma cells and the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 10b-c, 11b and 12b displayed the best anticancer activity with IC50 values between 0.131-0.183 mM and selectivity indices higher than 1 after 48 h of treatment. Selectivity indices were comparable to those reported for the reference drug, 5-fluorouracil (SI > 1). The SAR analysis showed that compounds with two carbon atom alkylic chains displayed the best activity (10b, 11b and 12b). Modeling studies including drug-likeness, bioactivity score and ADME/tox studies using online tools like molinspiration and Osiris suggested that these designed hybrids have a good pharmacological profile and can be considered as promising scaffolds for further studies in the search for new therapeutic alternatives to treat colorectal cancer.

Synthesis and in-vitro Evaluation of S-allyl Cysteine Ester - Caffeic Acid Amide Hybrids as Potential Anticancer Agents.

We have synthesized a series of S-allyl cysteine ester-caffeic acid amide hybrids and evaluated them in order to determine their possible anticancer activity and selectivity in colorectal cancer, which is still one of the leading causes of morbidity and mortality worldwide. All compounds were tested against SW480 human colon adenocarcinoma cells and the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 6e, 9a, 9b, 9c, and 9e exhibited the highest effect on viability (IC50 SW480-48h= 0.18, 0.12, 0.12, 0.11, and 0.12 mM, respectively) and selectivity (SI = 10.3, 1.5, >83.33, >90.91 and >83.33, respectively) in a time- and concentration-dependent manner. Besides, our results were even better as regards lead compounds (S-allyl cysteine and caffeic acid) and the standard drug (5-FU). Additionally, these five compounds induced mitochondrial depolarization that could be related with an apoptotic process. Moreover, hybrids 6e, 9a, and 9e induced cell cycle arrest in G2/M phase, and compound 9c in S- phase, which suggests that these hybrid compounds could have also a cytostatic effect in SW480 cell line. The SAR analysis showed that hydroxyl groups increased the activity. Besides, there was not a clear relationship between the antitumor properties and the length of the alkyl chain. Since hybrid compounds were much more selective than the conventional drug (5-FU), this makes them promising candidates for further studies against colorectal cancer.

Synthesis, leishmanicidal, trypanocidal and cytotoxic activity of quinoline-hydrazone hybrids.

Cutaneous leishmaniasis and Chagas disease are vector-borne parasitic disease causing serious risks to million people living in poverty-stricken areas. Both diseases are a major health problem in Latin America, and currently drugs for the effective treatment of these diseases have important concerns related with efficacy or toxicity than need to be addressed. We report herein the synthesis and biological activities (cytotoxicity, leishmanicidal and trypanocidal activities) of ten quinolone-hydrazone hybrids. The structure of the products was elucidated by spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis which is the most prevalent Leishmania species in Colombia and Trypanosoma cruzi that is the major pathogenic species to humans; in turn, cytotoxicity was evaluated against human U-937 macrophages. Compounds 6b, 6c and 8 showed activity against L. (V) panamensis with EC50 of 6.5 ± 0.8 µg/mL (21.2 µM), 0.8 ± 0.0 µg/mL (2.6 µM) and 3.4 ± 0.6 µg/mL (11.1 µM), respectively, while compounds 6a and 6c had activity against T. cruzi. with EC50 values of 1.4 ± 0.3 µg/mL (4.8 µM) and 6.6 ± 0.3 µg/mL (4.6 µM), respectively. Even compound 6a showed better activity against T. cruzi than the standard drug benznidazole with EC50 = 10.5 ± 1.8 µg/mL (40.3 µM). Analysis of the results obtained against leishmaniasis indicates that antiparasite activity is related to the presence of 2-substituted quinoline (isoquinolinic core) and the hydroxyl group in positions 3 and 4 of the aromatic ring. Although the majority of these compounds were highly cytotoxic, the antiparasite activity was higher than cytotoxicity and therefore, they still have potential to be considered as hit molecules for leishmanicidal and trypanocidal drug development.

Variables asociadas con la presentación de carne PSE (Pálida, Suave, Exudativa) en canales de cerdo / Variables associated PSE (Pale, Soft, Exudative) to meat in porcine carcasses

La presencia de la condición PSE (pálida, suave, exudativa) en canales porcinas causa altas pérdidas económicas a la industria cárnica y según estudios presenta asociación con muchas variables. Para analizarlas se muestrearon 474 canales de cerdos comerciales y se les midió el pH (pHmetro IQ 200 Scientific Instruments®, con sonda de silicio tipo ISFET®) a 45 minutos (pH45) y a 24 horas post-sacrificio en el músculo semimembranoso. Las variables analizadas fueron genética, sexo, alimento, tiempo de ayuno, peso vivo; duración del transporte, densidad, temperatura y humedad relativa durante el transporte; tipo de camión, tiempo de reposo, grasa dorsal, rendimiento en canal y mermas. En el análisis estadístico se aplicó la técnica de componentes principales, GLM con prueba de contraste de Tukey con un 95% de significancia, y distribución de frecuencias univariada y bivariada. Los resultados demuestran que hubo asociación altamente significativa (p<0.01) entre el pH45 y la densidad, alimento, camión, genética y reposo; el sexo y el tiempo de transporte tuvieron asociación significativa (p<0.05). Se encontró diferencia entre los tipos de genética, entre los sexos y entre los tipos de alimento (p<0.05). Se presentaron las interacciones sexo-ayuno, sexo-alimento, sexo-reposo y sexo-transporte (p<0.05). Esto indica que la condición PSE no es unicausal y como tal debe ser manejada.

The presence of the PSE (pale, soft and exudative) condition in porcine carcass causes high economic losses to the meat industry. The PSE appearance depends on many variables, some of which are intrinsic of the animal, and others are related to transportation conditions to the slaughterhouse. The aim of the present study was to determine if there is or not an association between some of the above mentioned variables and the PSE condition. The studied variables were: genetic, sex, food, weight, time of fasting, time of transportation, density, temperature and humidity during transportation, type of truck, resting time, dorsal fat, carcass efficiency and carcass weight losses. Carcasses of commercial genetic pigs (n = 474) were tested and semimembranous muscle pH was done at 45 minutes (pH45 ) and then at 24 h post-sacrifice, using IQ 200 Scientific Instruments®, with an ISFET® type probe. Test of principal components of GLM with contrast test of Tukey with 95% of significance, and univariate and divariate frequencies distribution was applied. The results demonstrate that there was highly significant association (p<0.01) between pH45 and variables as density, food, type of truck, genetic and the resting time. The sex and the time of transportation also had significant association (p<0.05), but only with pH45 . Additionally, differences between genetic, sex (highest values of pH45 to males) and food (p<0.05) were found. Also, there were interactions between: sex - fasting, sex - food, sex - resting and sex - transportation (p<0.05). According to the results, PSE condition is not a unicausal phenomenon and consequently it needs an integral managment.