Synthesis and in vitro evaluation of Ca 2+ channel blockers 1,4-dihydropyridines analogues against Trypanosoma cruzi and Leishmania amazonensis : SAR analysis

Pollo, Luiz A.E.; Moraes, Milene Höehr de; Cisilotto, Júlia; Creczynski-Pasa, Tânia Beatriz; Biavatti, Maique W.; Steindel, Mário; Sandjo, Louis P.

doi:10.1016/j.parint.2017.08.005

Cited by 11 publications

(14 citation statements)

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“…The biological assays were performed on intracellular amastigote form of the parasites L. amazonensis clinical cutaneous form (MHOM/BR/77/LTB0016) and the standard T. cruzi (Tulahuen strain found in Chilean triatomine bugs) as we previously reported (Pollo et al ., 2017). Therefore, T. cruzi trypomastigotes expressing β -galactosidase were grown in infected L929 cell line maintained at 37 °C, 5% CO 2 in RPMI-1640 medium supplemented with 5% FBS while L. amazonensis promastigotes expressing β -galactosidase were grown at 26 °C in Schneider's insect medium (Sigma Chemical Co., St. Louis, MO, USA) supplemented with heat inactivated 5% FBS and 2% human urine .…”

Section: Methodsmentioning

confidence: 99%

“…The human leukaemic THP-1 (ATCC TIB202) cell line used as a host cell was cultivated according to the protocol reported in the same previous work (Pollo et al ., 2017). This cell line was grown at 37 °C, 5% CO 2 , in RPMI-1640 without phenol red (Sigma-Aldrich, Co., St. Louis, MO, USA) supplemented with 10% FBS, HEPES 12.5 mm, penicillin (100 U mL −1 ), streptomycin (100 µ g mL −1 ) and Glutamax (2 mm).…”

Section: Methodsmentioning

confidence: 99%

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Antiprotozoal investigation of 20 plant metabolites on Trypanosoma cruzi and Leishmania amazonensis amastigotes. Atalantoflavone alters the mitochondrial membrane potential

et al. 2019

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The study aims to evaluate the antiprotozoal activities of 20 plant metabolites on Trypanosoma cruzi and Leishmania amazonensis amastigotes. Compounds 1–20 were obtained and identified by using chromatographic and spectroscopic techniques. The antiparasitic assays were performed on the intracellular form of T. cruzi and L. amazonensis using human leukaemic THP-1 cells as the host. The mechanism of action of the most active compounds was explored in silico by molecular docking using T. cruzi trypanothione reductase (TR) as a target, whereas the in vitro studies were performed by enzymatic assay using T. cruzi recombinant TR. In addition, the mitochondrial membrane potential was evaluated by flow cytometry. Two flavonoids, one triterpene and three acetogenins showed from high to moderate trypanocidal activities with IC50 values ranging 3.6–37.2 µm while three of the metabolites were moderately leishmanicidal. The molecular docking study revealed interactions between TR and the most trypanocidal compounds 1 (abyssinone IV) and 2 (atalantoflavone). In contrast, both showed no effect on TR in vitro. For the mitochondrial membrane potential assay, atalantoflavone (2) displayed a dose-dependent depolarization. On the basis of the aforementioned results, this compound's structure could be chemically explored in order to develop more potent trypanocidal derivatives.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Antiprotozoal investigation of 20 plant metabolites on Trypanosoma cruzi and Leishmania amazonensis amastigotes. Atalantoflavone alters the mitochondrial membrane potential

et al. 2019

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“…Human macrophage cell line THP‐1 (ATCC TIB202) was used as host for the intracellular amastigote forms of T. cruzi and L. amazoneneis . Cell viability assay (MTT) and antiparasitic in vitro evaluation were performed as we described …”

Section: Methodsmentioning

confidence: 99%

Prospecting for cytotoxic and antiprotozoal 4‐aryl‐4H‐chromenes and 10‐aryldihydropyrano[2,3‐f]chromenes

Martin

Mbaveng

Moraes

et al. 2018

Archiv der Pharmazie

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Different studies reported that genetic predisposition or metabolic dysfunction are the risk factors for cancer. Infectious parasitic diseases were listed among factors that predispose to cancer. Because of the resemblance between the life cycle of cancer cells and some parasites, this study aimed to prepare pyran derivatives with cytotoxic and antiprotozoal potencies. Therefore, 7 chromenes, 10 pyranocoumarins, and an unexpected intermediate were obtained from a multi-reagent one-pot reaction. These compounds were evaluated for their cytotoxicity on sensitive and resistant leukemia cancer cells lines and against two protozoan parasites, namely Trypanosoma cruzi and Leishmania amazonensis amastigote. Promising cytotoxicity (IC values of less than 1 µM) was obtained for two of the synthetic products (12 and 15). Compound 12 induced apoptosis and cell cycle arrest in CCRF-CEM leukemia cells in G0/G1 while compound 15 and doxorubicin induced apoptosis and arrest in the S and G2/M phases. Ten of these products showed trypanocidal activity, while only five of them were weakly active on L. amazonensis. Three of the obtained pyrans showed significant cytotoxicity and antitrypanocidal activity, simultaneously. Nevertheless, all antiparasitic compounds revealed potency with low selectivity toward THP-1 cells used as host.

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“…Ultimately, an effect on invading pathogens to limit natural selection of antibiotic-resistant strains would be a cost-effect efficiency goal ( Table 2 ). Calcium channel blockers have been studied in quinolone-resistant pneumococcal pneumonia [ 48 ], rifampicin-resistant tuberculosis [ 49 ], quinine-resistant Plasmodium falciparum malaria [ 50 , 51 ], and praziquantel-resistant Schistosoma mansoni infestation [ 52 , 53 ], amphotericin-resistant Leishmania donovani [ 54 ], and eflornithine-resistant Trypanosoma cruzi [ 55 ]. Benidipine may be useful for treatment of Toxoplasma gondii infestation for individuals allergic to sulfonamides like sulfadiazine or sulfamethoxazole [ 56 ].…”

Section: Antibiotic-resistant Pathogens May Utilize Channels Sensimentioning

confidence: 99%

Calcium Ion Channels: Roles in Infection and Sepsis Mechanisms of Calcium Channel Blocker Benefits in Immunocompromised Patients at Risk for Infection

D’Elia

Weinrauch

2018

IJMS

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Immunosuppression may occur for a number of reasons related to an individual’s frailty, debility, disease or from therapeutic iatrogenic intervention or misadventure. A large percentage of morbidity and mortality in immunodeficient populations is related to an inadequate response to infectious agents with slow response to antibiotics, enhancements of antibiotic resistance in populations, and markedly increased prevalence of acute inflammatory response, septic and infection related death. Given known relationships between intracellular calcium ion concentrations and cytotoxicity and cellular death, we looked at currently available data linking blockade of calcium ion channels and potential decrease in expression of sepsis among immunosuppressed patients. Notable are relationships between calcium, calcium channel, vitamin D mechanisms associated with sepsis and demonstration of antibiotic-resistant pathogens that may utilize channels sensitive to calcium channel blocker. We note that sepsis shock syndrome represents loss of regulation of inflammatory response to infection and that vitamin D, parathyroid hormone, fibroblast growth factor, and klotho interact with sepsis defense mechanisms in which movement of calcium and phosphorus are part of the process. Given these observations we consider that further investigation of the effect of relatively inexpensive calcium channel blockade agents of infections in immunosuppressed populations might be worthwhile.

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Synthesis and in vitro evaluation of Ca 2+ channel blockers 1,4-dihydropyridines analogues against Trypanosoma cruzi and Leishmania amazonensis : SAR analysis

Cited by 11 publications

References 20 publications

Antiprotozoal investigation of 20 plant metabolites on Trypanosoma cruzi and Leishmania amazonensis amastigotes. Atalantoflavone alters the mitochondrial membrane potential

Antiprotozoal investigation of 20 plant metabolites on Trypanosoma cruzi and Leishmania amazonensis amastigotes. Atalantoflavone alters the mitochondrial membrane potential

Prospecting for cytotoxic and antiprotozoal 4‐aryl‐4H‐chromenes and 10‐aryldihydropyrano[2,3‐f]chromenes

Calcium Ion Channels: Roles in Infection and Sepsis Mechanisms of Calcium Channel Blocker Benefits in Immunocompromised Patients at Risk for Infection

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