Novel semicarbazides and ureas of primaquine with bulky aryl or hydroxyalkyl substituents: Synthesis, cytostatic and antioxidative activity

Pavić, Kristina; Perković, Ivana; Cindrić, Maja; Pranjić, Marko; Martin-Kleiner, Irena; Kralj, Marijeta; Schols, Dominique; Hadjipavlou‐Litina, Dimitra; Katsori, Anna-Maria; Zorc, Branka

doi:10.1016/j.ejmech.2014.09.013

Cited by 28 publications

(37 citation statements)

References 28 publications

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“…MCF‐7 cells were sensitive to 15 of the 24 tested compounds, namely, 5 a – d , 2 d , 2 e , 4 a , 4 c – e , and 6 a – d . Similar results were obtained in our previous studies with various PQ derivatives . On the other hand, HepG2 cells were very robust and only responded towards 4 d and compounds from subclass 5 .…”

Section: Resultssupporting

confidence: 90%

“…Such observations prompted us, and others, to design and prepare novel derivatives of known antimalarial drugs and evaluate their cytostatic potential . Our efforts have been focused on primaquine (PQ), which is an old drug with many flaws (e.g., induction of hemolytic anemia in individuals lacking glucose‐6‐phosphate dehydrogenase, quick metabolism, degradation to inactive carboxyprimaquine, altering the treatment outcome in dependence of CYP 2D6 enzyme activity) but is currently the only available Plasmodium hypnozoitocide .…”

Section: Introductionmentioning

confidence: 99%

“…Our efforts have been focused on primaquine (PQ), which is an old drug with many flaws (e.g., induction of hemolytic anemia in individuals lacking glucose‐6‐phosphate dehydrogenase, quick metabolism, degradation to inactive carboxyprimaquine, altering the treatment outcome in dependence of CYP 2D6 enzyme activity) but is currently the only available Plasmodium hypnozoitocide . We previously showed that various PQ derivatives of amides, ureas, bis‐ureas, semicarbazides, and acylsemicarbazide‐type derivatives possessed significant cytostatic activity against a panel of cancer cell lines or high selectivity towards the breast adenocarcinoma cell line (MCF‐7) . On the other hand, cytostatic agents of different classes, including histone deacetylase (HDAC) inhibitors, have been shown to exert antiplasmodial activity .…”

Section: Introductionmentioning

confidence: 99%

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SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents

et al. 2018

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We report the synthesis of SAHAquines and related primaquine (PQ) derivatives. SAHAquines are novel hybrid compounds that combine moieties of suberoylanilide hydroxamic acid (SAHA), an anticancer agent with weak antiplasmodial activity, and PQ, an antimalarial drug with low antiproliferative activity. The preparation of SAHAquines is simple, cheap, and high yielding. It includes the following steps: coupling reaction between primaquine and a dicarboxylic acid monoester, hydrolysis, a new coupling reaction with O‐protected hydroxylamine, and deprotection. SAHAquines 5 a–d showed significant reduction in cell viability. Among the three human cancer cell lines (U2OS, HepG2, and MCF‐7), the most responsive were the MCF‐7 cells. The antibodies against acetylated histone H3K9/H3K14 in MCF‐7 cells revealed a significant enhancement following treatment with N‐hydroxy‐N′‐{4‐[(6‐methoxyquinolin‐8‐yl)amino]pentyl}pentanediamide (5 b). Ethyl (2E)‐3‐({4‐[(6‐methoxyquinolin‐8‐yl)amino]pentyl}carbamoyl)prop‐2‐enoate (2 b) and SAHAquines were the most active compounds against both the hepatic and erythrocytic stages of Plasmodium parasites, some of them at sub‐micromolar concentrations. The results of our research suggest that SAHAquines are promising leads for new anticancer and antimalarial agents.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents

et al. 2018

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“…Four PQ derivatives, namely N 1 ‐((4‐chlorophenyl)(phenyl)methyl)‐ N 2 ‐(4‐((6‐metoxyquinolin‐8‐yl)amino)pentyl)hydrazine‐1,2‐dicarboxamide ( 1 ), N 1 , N 2 ‐bis(4‐((6‐methoxyquinolin‐8‐yl)amino)pentyl)hydrazine‐1,2‐dicar‐boxamide ( 2 ), N 1 , N 1 ‐bis(2‐hydroxyethyl)‐ N 2 ‐(4‐((6‐methoxyquinolin‐8‐yl)amino)pentyl)hydrazine‐1,2‐dicarboxamide ( 3 ) and 1‐((4‐chlorophenyl)(phenyl)methyl)‐3‐(4‐((6‐methoxyquinolin‐8‐yl)amino)pentyl)urea ( 4 ) were prepared, according to our published procedure, in several synthetic steps, using the benzotriazole method . The spectral parameters (IR, 1 H and 13 C NMR and MS) of compounds 1 – 4 were in fully conformable with the previously published data.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro

Kędzierska

Orzelska

Perković

et al. 2015

Fundamemntal Clinical Pharma

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New primaquine (PQ) urea and semicarbazide derivatives 1-4 were screened for the first time for central nervous system (CNS) and antimalarial activity. Behavioural tests were performed on mice. In vitro cytotoxicity on L-6 cells and activity against erythrocytic stages of Plasmodium falciparum was determined. Compound 4 inhibited 'head-twitch' responses and decreased body temperature of mice, which suggests some involvement of the serotonergic system. Compound 4 protected mice against clonic seizures and was superior in the antimalarial test. A hybrid of two PQ urea 2 showed a strong antimalarial activity, confirming the previous findings of the high activity of bis(8-aminoquinolines) and other bisantimalarial drugs. All the compounds decreased the locomotor activity of mice, what suggests their weak depressive effects on the CNS, while PQ derivatives 1 and 2 increased amphetamine-induced hyperactivity. None of the compounds impaired coordination, what suggests a lack of their neurotoxicity. All the tested compounds presented an antinociceptive activity in the 'writhing' test. Compounds 3 and 4 were active in nociceptive tests, and those effects were reversed by naloxone. Compound 4 could be a useful lead compound in the development of CNS active agents and antimalarials, whereas compound 3 may be considered as the most promising lead for new antinociceptive agents.

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“…It follows from the literature survey, derivatives of semicarbazide and 1,2,4‐triazole can be used as anti‐inflammatory , antioxidant , antiparasitic , analgesic , anti‐HIV , antiviral , anticonvulsant , and antitumor agents. In addition, some of them also show antitubercular , antifungal , and antibacterial properties .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antimicrobial Evaluation of Novel Derivatives of Semicarbazide and 1,2,4‐triazole

Pachuta‐Stec

Biernasiuk

Malm

et al. 2017

Journal of Heterocyclic Chem

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Reaction of phenoxyacetic acid hydrazide with isocyanate was used to the synthesis of new semicarbazide derivatives. Cyclization of these compounds in a 2% aqueous solution of sodium hydroxide led to formation of 1,2,4‐triazole‐3‐one. The chemical structure of synthesized compounds was confirmed by elemental analysis and spectroscopic methods (1H and 13C NMR). On the basis of the NMR, spectra were found that cyclic compounds 1,2,4‐triazole exist in the ‐one form. Moreover, all derivatives were examined for their in vitro activity against some species of bacteria. New compounds presented mild or moderate antimicrobial activity only against reference Gram‐positive bacteria. Two derivatives (one semicarbazide and one triazole) showed bactericidal or bacteriostatic activity.

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Novel semicarbazides and ureas of primaquine with bulky aryl or hydroxyalkyl substituents: Synthesis, cytostatic and antioxidative activity

Cited by 28 publications

References 28 publications

SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents

SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents

Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro

Synthesis and Antimicrobial Evaluation of Novel Derivatives of Semicarbazide and 1,2,4‐triazole

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