Design, synthesis and in vitro trypanocidal and leishmanicidal activities of novel semicarbazone derivatives

Alves, Marina Amaral; Queiroz, Aline Cavalcanti de; Alexandre-Moreira, Magna Suzana; Varela, Javier; Cerecetto, Hugo; González, Mercedes; Doriguetto, Antônio C.; Landre, I. M. R.; Barreiro, Eliezer J.; Lima, Lı́dia Moreira

doi:10.1016/j.ejmech.2015.05.046

Cited by 18 publications

(12 citation statements)

References 38 publications

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“…The chemical stability of sulfonylhydrazones 4–9 in buffer solution with pH values that simulate gastric acid (pH =2.0) and serum content (pH 7.4) was investigated. 20 As shown in Figure 3A and B , all compounds presented great chemical stability, with the exception of compound 8 that was unstable at pH 2.0.…”

Section: Resultsmentioning

confidence: 91%

“…Compounds 4–9 were also studied in order to determine their plasma stability. 20 , 21 After 60 minutes incubation with rat plasma, compounds 4, 5, and 9 were very stable, while compounds 6, 7, and 8 were unstable ( Table 2 ). Only 2.2% and 9.6% of compounds 6 and 7, respectively, were recovered after plasma incubation, indicating the high lability of the ester subunit.…”

Section: Resultsmentioning

confidence: 98%

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Synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazones designed as anti-diabetic agents

Zapata‐Sudo

Nunes

Araujo

et al. 2016

DDDT

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Neuropathy is a serious complication of diabetes that has a significant socioeconomic impact, since it frequently demands high levels of health care consumption and compromises labor productivity. Recently, LASSBio-1471 (3) was demonstrated to improve oral glucose tolerance, reduce blood glucose levels, and display an anti-neuropathy effect in a murine streptozotocin-induced diabetes model. In the present work, we describe the design, synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazone derivatives (referred to herein as compounds 4–9), which were designed by molecular modification based on the structure of the prototype LASSBio-1471 (3). Among the compounds tested, better plasma stability was observed with 4, 5, and 9 in comparison to compounds 6, 7, and 8. LASSBio-1773 (7), promoted not only hypoglycemic activity but also the reduction of thermal hyperalgesia and mechanical allodynia in a murine model of streptozotocin-induced diabetic neuropathic pain.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 98%

Synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazones designed as anti-diabetic agents

Zapata‐Sudo

Nunes

Araujo

et al. 2016

DDDT

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“…The occurrence of common metabolic pathways in trypanosomatid parasites makes it potentially feasible to develop anti-protozoan agents endowed with a multi-trypanosomatid profile [14] , [55] . Thus, after having confirmed the significant activity against T. brucei of all the novel target heterofused quinoline derivatives and some of the ring-open analogues and assessed their brain permeation, cytotoxicity and AChE inhibitory activity, we undertook the evaluation of all the novel compounds against epimastigote forms of T. cruzi (strain MHOM/ES/2203/BCN590 (Tcl)) and promastigote forms of L. infantum (strain MCAN/ES/92/BCN722), using benznidazole and potassium antimony (III) tartrate hydrate as reference compounds.…”

Section: Resultsmentioning

confidence: 99%

“…Trypanosomatid parasites responsible for HAT, Chagas disease and visceral leishmaniasis seem to share common metabolic pathways [14] , [55] , thereby being potentially amenable to treatment by common drugs. Consistent with this, we have found some common SAR trends related to the activities of the novel tricyclic heterofused quinoline analogues against T. brucei , T. cruzi and L. infantum , with several of these compounds being moderately potent against two or three of these parasites.…”

Section: Discussionmentioning

confidence: 99%

Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity

Pietro

Vicente‐García

Taylor

et al. 2015

European Journal of Medicinal Chemistry

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Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[h][1,6]naphthyridines, pyrrolo[3,2-c]quinolines, azepino[3,2-c]quinolines, and pyrano[3,2-c]quinolines through 2–4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC50 values of 1.5 μM, 6.1 μM and 29.2 μM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC50 > 30 μM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.

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“…Procaspase-3 is the most common and key proapoptotic protein in the downstream apoptotic cascade, playing a significant role in the cancer development and progression. Procaspase-3 activators, which can directly induce apoptosis by activating over-expression procaspase-3 to caspase-3, [3][4][5][6][7][8] show greater advantages over anticancer agents targeting early or intermediate positions in the apoptotic cascade, such as p53 disruptors (CBL-0137 and COTI-2), [9][10][11] X-linked inhibitor of apoptosis protein (XIAP) inhibitors (AZD5582 and GDC-0152), 12,13) MDM2 inhibitors (HDM201 and RG7112), 14,15) and Bcl-2 inhibitors (GDC-0199 and ABT-737), 16,17) which likely resist the anticancer effects due to mutations of downstream apoptotic proteins.…”

Section: Introductionmentioning

confidence: 99%

Semicarbazone Derivatives Bearing Phenyl Moiety: Synthesis, Anticancer Activity, Cell Cycle, Apoptosis-Inducing and Metabolic Stability Study

Gao

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of semicarbazone derivatives bearing phenyl moiety were synthesized and evaluated for the vitro anticancer activities in four human cancer cell lines (human colon cancer (HT29), human neuroblastoma (SK-N-SH), human breast cancer (MDA-MB-231), and human gastric cancer (MKN45)). Biological evaluation led to the identification of 11q and 11s, which showed excellent anticancer activities against tested cancer cell lines with IC 50 values ranging from 0.32 to 1.57 µM, respectively, while exhibiting weak cytotoxicity on the normal cells (human umbilical vein endothelial cell (HUVEC)). Flow cytometric assay for cell cycle and apoptosis revealed that 11q and 11s caused an arrest in the Sub-G1 cell cycle and inhibited proliferation of cancer cells by inducing apoptosis in a dose-dependent manner. Further enzymatic assay suggested that 11q and 11s could significantly activated procaspase-3 to caspase-3. Metabolic stability study indicated that 11q and 11s showed moderate stability in vitro in human and rat liver microsomes. In view of promising pharmacological activities of 11q and 11s, which had emerged as the valuable lead for further development in the treatment for cancer.

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Design, synthesis and in vitro trypanocidal and leishmanicidal activities of novel semicarbazone derivatives

Cited by 18 publications

References 38 publications

Synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazones designed as anti-diabetic agents

Synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazones designed as anti-diabetic agents

Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity

Semicarbazone Derivatives Bearing Phenyl Moiety: Synthesis, Anticancer Activity, Cell Cycle, Apoptosis-Inducing and Metabolic Stability Study

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