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The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with Nα-protected amino acids, (ii) removal of the Nα-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t1/2 5–30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging. [Copyright &y& Elsevier]

Malaria is among the deadliest infectious diseases in the world caused by Plasmodium parasites. Due to the high complexity of the parasite's life cycle, we partly depend on antimalarial drugs to fight this disease. However, the emergence of resistance, mainly by Plasmodium falciparum, has dethroned most of the antimalarials developed to date. Given recent reports of resistance to artemisinin combination therapies, first-line treatment currently recommended by the World Health Organization, in Western Cambodia and across the Greater Mekong sub-region, it seems very likely that artemisinin and its derivatives will follow the same path of other antimalarial drugs. Consequently, novel, safe and efficient antimalarial drugs are urgently needed. One fast and low-cost strategy to accelerate antimalarial development is by recycling classical pharmacophores. Quinacrine, an acridine-based compound and the first clinically tested synthetic antimalarial drug with potent blood schizonticide but serious side effects, has attracted attention due to its broad spectrum of biological activity. In this sense, the present review will focus on efforts made in the last 20 years for the development of more efficient, safer and affordable antimalarial compounds, through recycling the classical quinacrine drug. [ABSTRACT FROM AUTHOR]

Ionic liquids derived from classical antimalarials are emerging as a new approach towards the cost-effective rescuing of those drugs. Herein, we disclose novel surface-active ionic liquids derived from chloroquine and natural fatty acids whose antimalarial activity in vitro was found to be superior to that of the parent drug. The most potent ionic liquid was the laurate salt of chloroquine, which presented IC50 values of 4 and 110 nM against a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum, respectively, corresponding to an 11- and 6-fold increase in potency as compared to the reference chloroquine bisphosphate salt against the same strains. This unprecedented report opens new perspectives in both the fields of malaria chemotherapy and of surface-active ionic liquids derived from active pharmaceutical ingredients. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two families of N -cinnamoyl-aminoacridine conjugates are proposed as antiproliferative leads. • One family of conjugates showed in vitro activity against three cancer cell lines in the micromolar range. • Two conjugates showed better antiproliferative activity in vitro than reference drugs. • The most promising conjugates were highly selective, showing no toxicity to non-carcinogenic cells. Drug repurposing and rescuing have been widely explored as cost-effective approaches to expand the portfolio of chemotherapeutic agents. Based on the reported antitumor properties of both trans- cinnamic acids and quinacrine, an antimalarial aminoacridine, we explored the antiproliferative properties of two series of N -cinnamoyl-aminoacridines recently identified as multi-stage antiplasmodial leads. The compounds were evaluated in vitro against three cancer cell lines (MKN-28, Huh-7, and HepG2), and human primary dermal fibroblasts. One of the series displayed highly selective antiproliferative activity in the micromolar range against the three cancer cell lines tested, without any toxicity to non-carcinogenic cells. [ABSTRACT FROM AUTHOR]

Abstract: Primaquine was firstly synthesized in 1946 in the USA, and is the most representative member of the anti-malarial 8-aminoquinolines. Six decades have passed and primaquine is still the only transmission-blocking anti-malarial clinically available, displaying a marked activity against gametocytes of all species of human malaria, including multi-resistant Plasmodium falciparum strains. Primaquine is also effective against all exoerythrocytic forms of the parasite and is used in conjunction with other anti-malarials for the treatment of vivax and ovale malaria. However, primaquine is often associated with serious adverse effects, in consequence of its toxic metabolites. 5-Hydroxyprimaquine or 6-methoxy-8-aminoquinoline has been considered to be directly responsible for complications such as hemolytic anemia. Primaquine toxicity is aggravated in people deficient of 6-glucose phosphate dehydrogenase or glutathione synthetase. Adverse effects are further amplified by the fact that primaquine must be repeatedly administered at high doses, due to its limited oral bioavailability. Over the last two decades, Medicinal Chemists have battled against primaquine''s disadvantages, while keeping or even improving its unequalled performance as an anti-malarial. The present text revisits primaquine and its properties on the occasion of its 60th anniversary and aims to give a general overview of what has been the path towards the development of effective and safe primaquine-based anti-malarials. Presently, aablaquine and tafenoquine the two most promising primaquine analogues are already in the final stages of clinical trials against Plasmodium vivax and P. falciparum. Both compounds are a new hope against malaria and other primaquine-sensitive illnesses, such as Pneumocystis Pneumonia or the Chagas disease. [Copyright &y& Elsevier]

Graphical abstract Highlights • Unprecedented 9-step route towards N 4, N 9-disubstituted 4,9-diaminoacridines, starting from 4-chlorosalicylic acid. • Insertion of the N 9-substituent prior to the N 4-substituent is preferable. • Nitro-aniline reduction step could only be achieved by using SnCl 2 /aq. HCl. • Target structures combine the pharmacophores of mepacrine, chloroquine and primaquine, three classical antimalarial drugs. Abstract A multi-step synthetic route towards N 4, N 9-disubstituted 4,9-diaminoacridines that, to the best of our knowledge, has no precedence in the literature, has been developed. The target structures are likely to reveal interesting biological activities in the near future, not only due to their mepacrine-like core, but also because they embed simultaneously the pharmacophores of chloroquine and primaquine, antimalarial drugs that act at different stages of malaria infection. [ABSTRACT FROM AUTHOR]

Malaria, leishmaniasis and Chagas disease are vector-borne protozoal infections with a disproportionately high impact on the most fragile societies in the world, and despite malaria-focused research gained momentum in the past two decades, both trypanosomiases and leishmaniases remain neglected tropical diseases. Affordable effective drugs remain the mainstay of tackling this burden, but toxicicty, inneficiency against later stage disease, and drug resistance issues are serious shortcomings. One strategy to overcome these hurdles is to get new therapeutics or inspiration in nature. Indeed, snake venoms have been recognized as valuable sources of biomacromolecules, like peptides and proteins, with antiprotozoal activity. This review highlights major snake venom components active against at least one of the three aforementioned diseases, which include phospholipases A2, metalloproteases, L-amino acid oxidases, lectins, and oligopeptides. The relevance of this repertoire of biomacromolecules and the bottlenecks in their clinical translation are discussed considering approaches that should increase the success rate in this arduous task. Overall, this review underlines how venom-derived biomacromolecules could lead to pioneering antiprotozoal treatments and how the drug landscape for neglected diseases may be revolutionized by a closer look at venoms. Further investigations on poorly studied venoms is needed and could add new therapeutics to the pipeline. [Display omitted] [ABSTRACT FROM AUTHOR]

Most drugs currently entering the clinical pipeline for severe malaria therapeutics are of lipophilic nature, with a relatively poor solubility in plasma and large biodistribution volumes. Low amounts of these compounds do consequently accumulate in circulating Plasmodium -infected red blood cells, exhibiting limited antiparasitic activity. These drawbacks can in principle be satisfactorily dealt with by stably encapsulating drugs in targeted nanocarriers. Here this approach has been adapted for its use in immunocompetent mice infected by the Plasmodium yoelii 17XL lethal strain, selected as a model for human blood infections by Plasmodium falciparum . Using immunoliposomes targeted against a surface protein characteristic of the murine erythroid lineage, the protocol has been applied to two novel antimalarial lipophilic drug candidates, an aminoquinoline and an aminoalcohol. Large encapsulation yields of >90% were obtained using a citrate-buffered pH gradient method and the resulting immunoliposomes reached in vivo erythrocyte targeting and retention efficacies of >80%. In P. yoelii -infected mice, the immunoliposomized aminoquinoline succeeded in decreasing blood parasitemia from severe to uncomplicated malaria parasite densities (i.e. from ≥25% to ca. 5%), whereas the same amount of drug encapsulated in non-targeted liposomes had no significant effect on parasite growth. Pharmacokinetic analysis indicated that this good performance was obtained with a rapid clearance of immunoliposomes from the circulation (blood half-life of ca. 2 h), suggesting a potential for improvement of the proposed model. [ABSTRACT FROM AUTHOR]

Primaquine-based ionic liquids, obtained by acid-base reaction between parent primaquine and cinnamic acids, were recently found as triple-stage antimalarial hits. These ionic compounds displayed significant activity against both liver- and blood-stage Plasmodium parasites, as well as against stage V P. falciparum parasites. Remarkably, blood-stage activity of the ionic liquids against both chloroquine-sensitive (3D7) and resistant (Dd2) P. falciparum strains was clearly superior to those of the respective covalent (amide) analogues and of parent primaquine. Having hypothesized that such behaviour might be ascribed to an enhanced ability of the ionic compounds to permeate into Plasmodium -infected erythrocytes, we have carried out a differential scanning calorimetry-based study of the interactions between the ionic liquids and membrane models. Results provide evidence, at the molecular level, that the primaquine-derived ionic liquids may contribute to an increased permeation of the parent drug into malaria-infected erythrocytes, which has relevant implications towards novel antimalarial approaches based on ionic liquids. [ABSTRACT FROM AUTHOR]

The article presents brief information on recycling of drugs for malaria. Topics discussed include chemical recycling of quinine, synthetic blood-stage antimalarial acridines named Quinacrine, and synopsis of clinically relevant antimalarial 4-aminoquinolines. Also talks about computational studies on antimalarial classics and their analogues, and rescuing and repurposing drugs used in malaria such as antitumorals and antiretrovirals.

Abstract: The growth inhibitory activity of imidazoquines, antimalarial imidazolidin-4-ones derived from primaquine, on human cancer cell lines HT-29, Caco-2, and MCF-7 has been evaluated. Primaquine, N-dipeptidyl-primaquine derivatives, and other quinolines have been included in the study for comparison purposes. Primaquine and some of its derivatives were significantly active against the MCF-7 human breast cancer cell line, so these compounds might represent useful leads targeted at the development of novel specific agents against breast cancer. Conversely, all compounds were generally inactive against HT-29, with only one of the imidazoquines having IC50 below 50μM. Activities against the Caco-2 cell line were modest and did not follow any defined trend. [Copyright &y& Elsevier]

Abstract: Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus were synthesized and evaluated as potential transmission-blocking antimalarial prodrugs. All compounds were hydrolyzed to the parent dipeptide derivative of primaquine in neutral and basic solutions, with half lives ranging from 0.7 to 31h at 37°C, depending on the nature of the substituents present in the imidazolidin-4-one moiety and in the C-terminal amino acid directly coupled to primaquine. The antimalarial activity was studied for selected compounds using a model consisting of Plasmodium berghei, BalbC mice and Anopheles stephensi mosquitoes. The imidazolidin-4-one derived from Ala-Ala–primaquine and acetone reduced the transmission of the infection to mosquitoes more efficiently than primaquine as shown by the significant decrease in the number of oocysts in the midguts of the mosquitoes at 10 and 50μmol/kg when compared to the control. [Copyright &y& Elsevier]

Electrospray ionization-ion trap mass spectrometry (ESI-MS) of imidazolidin-4-one peptidomimetic derivatives of the antimalarial drug primaquine (PQ) is reported. These compounds contain the imidazolidin-4-one moiety either at the N- or the C-terminal of a dipeptide backbone, thus respectively mimicking PQ-Amino Acid-Proline (PQAAPro) and PQProAA derivatives of PQ. Both the peptidomimetics and precursors previously developed by us are promising drug candidates, as they were found to be active against rodent Plasmodium berghei malaria and Pneumocystis carinii pneumonia. Collision-induced dissociation (CID) and tandem-mass spectra (MS) of the title compounds, and fragmentation pathways thereof, led to the following findings: (1) CID patterns present some parallelism with the reactivity towards hydrolysis previously found for the same or related compounds; (2) a positional shift of the imidazolidin-4-one ring is reflected on both degree and pathways of fragmentation, which makes tandem-MS a key tool for differentiation of imidazolidin-4-one isomers; (3) the major MS/MS fragmentation of PQProAA mimetics involves release of a neutral diketopiperazine (DKP), in parallel to the “diketopiperazine pathway” described in tandem-MS studies of oligopeptides; (4) the relative abundance of a major fragment in tandem-MS spectra is inversely correlated with the size of the N-terminal AA in PQProAA mimetics. Overall, this work embodies an original and valuable contribution towards a deeper insight into the molecular properties of novel antimalarials, which can be viewed as representative of both the 8-aminoquinoline and, especially, the imidazolidin-4-one structural classes. [Copyright &y& Elsevier]

Abstract: The synthesis of imidazolidin-4-one derivatives of primaquine containing the five-membered ring at the C-terminus of a dipeptide backbone coupled to the parent drug is described. These peptidomimetic derivatives were active against a chloroquine-resistant Plasmodium falciparum strain and inhibited the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The novel imidazolidin-4-ones are extremely stable, both in human plasma and in pH 7.4 buffer, as a result of N1-acylation. Thus, ‘internal’ imidazolidin-4-ones derived from dipeptidyl 8-aminoquinolines represent a new entry in antimalarial structure–activity relationships. [Copyright &y& Elsevier]

Abstract: A series of primaquine-derived imidazolidin-4-ones were screened for their in vitro activity against Pneumocystis carinii and Plasmodium falciparum W2 strain. Most compounds were active against P. carinii above 10μg/mL and displayed slight to marked activity. The imidazolidin-4-ones most active against P. carinii were also those most active antiplasmodial agents, in the μM range. One of the tested imidazolidin-4-ones was slightly more active than the parent primaquine and may represent a lead compound for the development of novel anti-P. carinii 8-aminoquinolines with increased stability and resistance to metabolic inactivation. [Copyright &y& Elsevier]