Primaquine hybrids as promising antimycobacterial and antimalarial agents

Pavić, Kristina; Perković, Ivana; Pospíšilová, Šárka; Machado, Marta; Fontinha, Diana; Prudêncio, Miguel; Jampílek, Josef; Coffey, Aidan; Endersen, Lorraine; Rimac, Hrvoje; Zorc, Branka

doi:10.1016/j.ejmech.2017.11.083

Cited by 33 publications

(27 citation statements)

References 56 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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“…These compounds were active against P. falciparum while exhibiting a very favourable toxicity profile towards human cells in vitro, which was retained even when the glucose-6-phosphate dehydrogenase (G6PD) was inhibited. On the other hand, bis-ureas 90, 93 and 76 with p-chlorobenzene, p-CF 3 -benzene and dimethoxybenzhydryl moieties displayed antiplasmodial activity in vitro against liver stage P. berghei in the nanomolar scale (IC 50 ¼ 42.0, 74.9 and 82.8 nM) [109]. Compound 93 showed antiproliferative activity in low micromolar concentrations as well.…”

Section: Antiplasmodial Evaluationmentioning

confidence: 99%

“…Antiplasmodial screening was performed in vitro and in vivo (only for the selected compounds). Five subsets of PQ derivatives with amide or urea moieties (57 compounds) were evaluated for antiplasmodial activity in vitro against the erythrocytic stage of P. falciparum NF54 [93,109,110]. Out of them, 33 compounds showed weak activity (IC 50 ¼ 10e20 mM) and 7 compounds strong activity in low micromolar range.…”

Section: Antiplasmodial Evaluationmentioning

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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Selective α‐Deuteration of Cinnamonitriles using D₂O as Deuterium Source

2021

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The selective α-deuteration of α,β-unsaturated nitriles using the strong base t BuOK or a metalligand cooperative Ru pincer catalyst is described. With D 2 O as deuterium source and glyme as solvent at 70 °C, t BuOK is an efficient catalyst for deuteration at the α-C(sp 2 ) position of cinnamonitriles, providing access to a broad range of deuterated derivatives in good to excellent yields and with very high levels of deuterium incorporation. While the t BuOK-catalysed protocol does not tolerate base-sensitive functional groups, cinnamonitrile derivatives containing a benzylic bromide or ester moiety were deuterated in excellent yields using Milstein's ruthenium PNN pincer catalyst. Moreover, the activity for H/D exchange of the metalligand cooperative Ru catalyst is found to be significantly higher than that of t BuOK, allowing reactions to proceed well even at room temperature. A mechanistic proposal is put forward that involves deprotonation of the cinnamonitrile α-CH position when using t BuOK as catalyst, whereas H/D exchange catalysis with the Ru PNN pincer likely proceeds via (reversible) oxa-Michael addition of D 2 O.

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Primaquine hybrids as promising antimycobacterial and antimalarial agents

Cited by 33 publications

References 56 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

Selective α‐Deuteration of Cinnamonitriles using D₂O as Deuterium Source

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Primaquine hybrids as promising antimycobacterial and antimalarial agents

Cited by 33 publications

References 56 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

Selective α‐Deuteration of Cinnamonitriles using D2O as Deuterium Source

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Product

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Selective α‐Deuteration of Cinnamonitriles using D₂O as Deuterium Source