Novel urea and bis -urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents: Synthesis and biological evaluation

Perković, Ivana; Antunović, Maja; Marijanović, Inga; Pavić, Kristina; Ester, Katja; Kralj, Marijeta; Vlainić, Josipa; Kosalec, Ivan; Schols, Dominique; Hadjipavlou‐Litina, Dimitra; Pontiki, Eleni; Zorc, Branka

doi:10.1016/j.ejmech.2016.08.021

Cited by 31 publications

(31 citation statements)

References 30 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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“…Another set of urea derivatives (38, 39, 43e52) was prepared in the opposite way, by the reaction of primaquine with the active ureas BtcNRR 1 , obtained from BtcCl and various amines [80,83]. Only urea 42 was synthesized by the classic isocyanate method, e.g.…”

Section: Primaquine Amide Carbamate Urea and Semicarbazide Derivativesmentioning

confidence: 99%

“…Syntheses of bis-urea derivatives were more complex. Two synthetic methods for the bis-ureas growing from the PQ side were applied: i) the reaction of the active ureas BtcNRR 1 with the common precursor 61 (bis-ureas 75, 76) [80]; ii) the reaction of various amines with the active bis-urea intermediate obtained from 61 and BtcCl (bis-ureas 73, 74, 77, 78, 80e94, 100e104) [80,81,83]. When primaquine was used as an amine, symmetric bis-urea 78 bearing two primaquine moieties was prepared.…”

Section: Primaquine Amide Carbamate Urea and Semicarbazide Derivativesmentioning

confidence: 99%

Primaquine derivatives: Modifications of the terminal amino group

Zorc

Perković

Rajić

et al. 2019

European Journal of Medicinal Chemistry

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a b s t r a c tNumerous modifications of the well-known antimalarial drug primaquine, both at the quinoline ring and at the primary amino group, have been reported, mostly to obtain antimalarial agents with improved bioavailability, reduced toxicity and/or prolonged activity. Modifications of the terminal amino group were made with the main idea to prevent the metabolic pathway leading to inactive and toxic carboxyprimaquine (follow-on strategy), but also to get compounds with different activity (repurposing strategy). The modifications undertaken until 2009 were included in a review published in the same year. The present review covers various classes of primaquine N-derivatives with diverse biological profiles, prepared in the last decade by our research group as well as the others. We have summarized the synthetic procedures applied for their preparation and discussed the main biological results. Several hits for the development of novel antiplasmodial, anticancer, antimycobacterial and antibiofilm agents were identified.

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Synthesis, characterization, and biological evaluations of substituted phenethylamine-based urea as anticancer and antioxidant agents

Özgeriş

2021

Monatsh Chem

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Novel urea and bis -urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents: Synthesis and biological evaluation

Cited by 31 publications

References 30 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

Primaquine derivatives: Modifications of the terminal amino group

Synthesis, characterization, and biological evaluations of substituted phenethylamine-based urea as anticancer and antioxidant agents

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