Leishmaniases are a complex of tropical and sub-tropical diseases caused by parasites of the genus Leishmania and transmitted by the bite of an insect vector, the sandfly. Quinolines of natural origin have shown interesting antileishmanial activities on several experimental leishmaniasis models. A classical daily treament with 2-n-propylquinoline (2-n-PQ) on five consecutive days in mice model is not sufficient to cure the mice infected with Leishmania donovani and the activity requires a 10-day treatment duration whatever the route (oral, parenteral) because of a short half-life elimination of the drug.

Therefore, 2-n-PQ derivatives were bound to soluble polysaccharides to improve their solubility, delay their elimination half-life and therefore enhance the activity. In vitro release at 37ºC in phosphate buffer was performed in various conditions and showed that around 65% of the compound was released in 24 h. In vitro, the most active conjugate was the dextran-2PQA conjugate exhibiting an IC₅₀ value at 12 µg/mL on Leishmania donovani intramacrophage amastigotes. However, this system did not allow a sufficient release of the active principle explaining the lack of in vivo activity.

Another approach consisted in administering 2-n-PQ intravenously. Two systems were successful both in vitro and in vivo : a liposomal formulation named 2-n-PQ-LIP and a hydroxypropyl beta-cyclodextrin inclusion complex designated as 2-n-PQ-HPC. The most interesting one was the liposomal formulation, active on the L. donovani Balb/c mouse model, by reducing the parasite burden by more than 80% after an intravenous treatment regimen of 3 mg equivalent 2-n-PQ/kg/day given on five consecutive days. No synergistic activity between 2-n-PQ and Amphotericin B was monitored either in vitro or in vivo.

These formulations should be studied further on other leishmaniasis models and for toxicological considerations.

Acknowledgements

This work was supported by a grant from the Indo-French Centre of Advanced Research, New Delhi (CEFIPRA) (No. 4803-04) and Kaluvu Balaraman was recipient of a CEFIPRA postdoctoral fellowship.

VEP nucleosides bypass two mechanisms of tumor resistance: nucleoside transport and kinase downregulation.  Isoforms of VE have shown activity against solid and hematologic tumors.  Gemcitabine was conjugated at the 5’ position to either δ-tocopherol-MP (NUC050) or δ-tocotrienol-MP (NUC052).

NUC050 has been demonstrated to deliver gemcitabine-MP intracellularly.  Its half-life IV in mice is 3.9 compared to 0.28 hours for gemcitabine (European J Cancer. 2016. 61(Suppl. 1):S119).

When tumors in nude mice reached 32 to 75 mg mm³ (day 4) treatment was initiated with gemcitabine (120 mg/kg IP q3dx9), NUC050 or NUC052 (both 40 mg/kg qwkx4) and compared to saline control (SC).

Gemcitabine inhibited tumor growth but was not tolerated.  NUC050 resulted in inhibition to tumor growth on days 11-31 (p<0.05), with a nadir of -73% compared to SC.  Median survival was 25.5 days (SC) vs 33 days (NUC050) ((hazard ratio) HR=0.24, p=0.017).  NUC052 had the dose increased to 50 mg/kg after 2 doses.  NUC052 resulted in inhibition to tumor growth on days 14-27 (p<0.05), with a nadir of -45%, and median survival was 34 days (HR=0.27, p=0.033).

NUC050 and NUC052 have been shown to be safe and effective in a NSCLC xenograft.  Studies have been initiated in a pancreatic cancer xenograft.

In this study, the cytotoxic effects of different squaramides were tested against diverse cancer cells, such as HGC-27, HeLa, T98 and U87 cells, and non-cancer cells, such as EK293, MDCK and Vero cells. The best results were observed in a disubstituted squaramide that showed an IC₅₀ of 1.81 μM against HGC-27 cells, which is a considerably lower value than the IC₅₀ values observed in the rest of the cell lines. Therefore, this squaramide and its derivatives could be promising molecules for the treatment of gastric carcinoma.

Furthermore, the mechanism of action of this compound was evaluated. The outcomes indicated that the decrease in cell viability produced by the squaramide is probably caused by G₀/G₁ cell cycle arrest and caspase-mediated apoptosis. Additionally, the cell death produced by this compound was accompanied by autophagy induction and no signs of cathepsin-mediated cell death and necroptosis were observed.

Alimentary obesity is an important social problem for all developed countries. A variety of factors affects gain of body weight. among which hypodynamia, which is caused by widespread automation. To date, the human diet increases the palm oil content due to its low cost and long shelf life. Detailed research of the effect of excessive amount of palm oil on the body state is very relevant. In the modern world, it is important to search for highly effective and safe medicines for weight loss treatment of metabolic syndrome consequences. 

This work is dedicated to a search for effective and safe  pharmacorrection medications for the first-degree obesity treatment, as the result of excessive consumption of palm oil during a long period of time. 

Our studies have shown that two new compounds containing chalcogenamide groups have the property of reducing weight. The experiment was performed on 24 white non-linear sexually mature rats of both sexes, which weighed 120-180g. The animals were divided into 4 groups. The animals of the intact group were kept on a standard diet of the vivarium of the State Institution «Lugansk State Medical University», LPR. The second group, the control group, has been receiving palm oil at a dose of 30 g/kg to a daily ration for a period of 6 weeks. The rats of the third and fourth groups have been receiving samples of two new organic compounds 1 and 2).The compounds were administered intragastrically at a dose of 2.5 mg/kg for 2 weeks after a six-week high-fat diet. Once every 7 days the rats were weighed to assess the dynamics of changes in their weight.

The body weight of animals had increased by 121% after a six-week high-fat diet. After the first week of pharmacorrection, the  third group showed a decrease in weight by 12.17%, and after the second week the animals lost another 10.75%. During the two-week period of administration of the substance 1 the weight of the rats decreased by a factor of 1,27 and approached the values of the body weight of animals of the intact group. There were no animal deaths in this group, the behavioral reactions of rats were adequate. In the latter days of research the flabbiness of the hair-coat was noted. In the fourth experimental group, the mass decreased by 8.02% during the first two-week period. The death of animals was absent, behavioral reactions were adequate.

The performed studies have shown that substances  1 {3',9'-dibenzyl-6'-selenoxo-3',4',9',10'- tetrahydro-2'H-spiro[cyclohexane-1,12'-[1,3,5,9] tetraaza[7,11]-methano[1,3,5]triazino[1,2-a] [1,5]diazocine]-7',11'(6'H,8'H)-dicarbonitrile} and 2 {4-(2-chlorophenyl)-2-({[3-methyl-2,6-dioxo-7-(2-oxo- 2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl} thio)-5,6,7,8-tetrahydroquinoline-3-carbonitrile} possessed the properties of prospective pharmacorrection medications for alimentary obesity treatment.

Chagas disease is caused by the parasite Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America, despite recent advances in the control of its vector-borne and transfusion mediated transmission. Moreover, migration of infected people has spread the disease to non-endemic areas, presenting a new worldwide challenge. The chemotherapy employed to control the parasitic infection is based on two drugs: Nifurtimox (Nfx) and Benznidazole (Bnz), requiring long-term treatment that can give rise to severe side effects. They are not active against all T. cruzi strains, exhibit low efficiency in long-term chronic infections, and are mutagenic.  The search of new drugs is an urgent need. In this work, we used three symmetrical diarylideneketones containing thiophene and furane ((1E,3E,6E,8E)-1,9-Di(furan-2-yl)nona-1,3,6,8-tetraen-5-one (1), (2E,6E)-2,6-Bis((E)-3-(furan-2-yl)allylidene)cyclohexanone (2) and (2E,5E)-2,5-Bis[3-(thiophen-2-yl)allyliden]cyclopentanone (3)). These molecules showed good to excellent trypanosomicidal activity and selectivity to the parasite, affected cruzipain, a proteolytic enzyme of the parasite, and the glycolytic enzyme, triosephosphate isomerase of T. cruzi (TcTIM) without affecting human´s TIM and showing effectiveness in protecting infected mice and without  toxic effects in vivo. In addition, these could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases. The type of T. cruzi death caused is an important feature to determine, because it could govern inflammation events unbeneficial in the elimination of the parasite. We studied the mechanism of T. cruzi death using Annexin V and propidium iodide followed by flow cytometry analysis of epimastigote treated with the arylideneketones (1, 2, and 3). The arylideneketones along with Nfx and Bnz were evaluated at 24 h post- incubation with the parasite at 5X,  10X and 20X IC₅₀. Arylidenketones 1 and 2 causes after 24 h late apoptosis/necrosis at a concentration of 20 times the value of its IC₅₀ (approximately 80% of late apoptosis/necrosis) as Nfx. This necrotic effect of Nfx was also observed in our previous study by TUNNEL and ¹H NMR. It should be studied what happens with compound 3 since no death is observed by apoptosis or necrosis at a dose of 20 times the value of their IC₅₀ as Bnz. Probably, an autophagy process could be ongoing. Currently, we are performing studies in this sense.

Acknowledgments: This work was supported by CSIC, PEDECIBA and Elena Aguilera is recipient of a ANII doctoral fellowship.