Novel Endoperoxide-Based Transmission-Blocking Antimalarials with Liver- and Blood-Schizontocidal Activities

Miranda, Daniela; Capela, Rúben A.; Albuquerque, Inês S.; Meireles, Patrícia; Paiva, Isa; Nogueira, Fátima; Amewu, Richard K.; Gut, Jiří; Rosenthal, Philip J.; Oliveira, Rudi; Mota, Maria M.; Moreira, Rui; Martí, Francesc; Prudêncio, Miguel; O’Neill, Paul M.; Lopes, Francisca

doi:10.1021/ml4002985

Cited by 40 publications

(34 citation statements)

References 38 publications

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“…To seek for capable candidates against both the blood‐ and liver‐stages of malaria parasites, three PQ‐ART hybrids 5 (Figure ) were designed, synthesized, and evaluated for their multistage antiplasmodial activities against CQR W2 P falciparum and Plasmodium berghei strains . All hybrids (IC 50 : 5.1‐523 nM) were highly active against both erythrocytic (CQR W2 P falciparum ) and exoerythrocytic ( P berghei ) forms of malaria parasites, and they were comparable to ART (IC 50 : 8.2 nM) against erythrocytic stage of P falciparum , 14 to 647 times more potent than PQ (IC 50 : 3300 and 7500 nM) against erythrocytic stage of P falciparum and exoerythrocytic stage of P berghei .…”

Section: Quinoline‐artemisinin (Or Its Derivatives) Hybrids (Type I)mentioning

confidence: 99%

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Feng

Chang

et al. 2019

Medicinal Research Reviews

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Malaria is a tropical disease, leading to around half a million deaths annually. Antimalarials such as quinolines are crucial to fight against malaria, but malaria control is extremely challenged by the limited pipeline of effective pharmaceuticals against drug-resistant strains of Plasmodium falciparum which are resistant toward almost all currently accessible antimalarials. To tackle the growing resistance, new antimalarial drugs are needed urgently. Hybrid molecules which contain two or more pharmacophores have the potential to overcome the drug resistance, and hybridization of quinoline privileged antimalarial building block with other antimalarial pharmacophores may provide novel molecules with enhanced in vitro and in vivo activity against drug-resistant (including multidrug-resistant) P falciparum. In recent years, numerous of quinoline hybrids were developed, and their activities against a panel of drug-resistant P falciparum strains were screened. Some of quinoline hybrids were found to possess promising in vitro and in vivo potency. This review emphasized quinoline hybrid molecules with

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Section: Quinoline‐artemisinin (Or Its Derivatives) Hybrids (Type I)mentioning

confidence: 99%

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Feng

Chang

et al. 2019

Medicinal Research Reviews

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“…Hybrid molecules capable of hitting more than one molecular target are an attractive alternative to currently approved antimalarial drugs. Thus, two antiplasmodial drugs with different modes of action, primaquine and artemisinin, were combined in hybrids 162e164 [119,120]. Amine and amide covalent bonds between primaquine and artemisinin were achieved according to the procedures presented in Scheme 9.…”

Section: Primaquine-artemisinin Conjugatesmentioning

confidence: 99%

“…A small library of hybrid compounds 165e168 combining 1,2,4,5-tetraoxane (endoperoxide system similar to 1,3,4-trioxane present in artemisinin) and primaquine or other 8aminoquinoline moieties was prepared and screened for the antimalarial activity (Scheme 10) [120,121]. These hybrids showed high potency against both exoerythrocytic and erythrocytic forms of malaria parasites and efficiently blocked the development of the sporogonic cycle in the mosquito vector.…”

Section: Primaquine-artemisinin Conjugatesmentioning

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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“…Miranda et al (18) reported a series of hybrid compounds combining either a 1,2,4-trioxane or 1,2,4,5-tetraoxane and 8-aminoquinoline moieties. The hybrids were synthesized and screened for their antimalarial activity.…”

Section: Advantages Of Hybridsmentioning

confidence: 99%

“…• Nature of the linker unit employed Figure 1 illustrates a detailed classification of hybrids based on the categories listed above, along with an example of a hybrid compound in each category (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

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confidence: 99%

Are Antimalarial Hybrid Molecules a Close Reality or a Distant Dream?

Agarwal

Gupta

Awasthi

2017

Antimicrob Agents Chemother

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Emergence of drug-resistant Plasmodium falciparum strains has led to a situation of haste in the scientific and pharmaceutical communities. Hence, all their efforts are redirected toward finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. In light of this situation, scientists have come up with the concept of hybridization of two or more active pharmacophores into a single chemical entity, resulting in "antimalarial hybrids." The approach has been applied widely for generation of lead compounds against deadly diseases such as cancer and AIDS, with a proven potential for use as novel drugs, but is comparatively new in the sphere of antimalarial drug discovery. A sudden surge has been evidenced in the number of studies on the design and synthesis of hybrids for treating malaria and may be regarded as proof of their potential advantages over artemisinin-based combination therapy (ACT). However, it is evident from recent studies that most of the potential advantages of antimalarial hybrids, such as lower toxicity, better pharmacokinetics, and easier formulation, have yet to be realized. A number of questions left unaddressed at present need to be answered before this approach can progress to the late stages of clinical development and prove their worth in the clinic. To the best of our knowledge, this compilation is the first attempt to shed light on the shortcomings that are surfacing as more and more studies on molecular hybridization of the active pharmacophores of known antimalarials are being published.

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Novel Endoperoxide-Based Transmission-Blocking Antimalarials with Liver- and Blood-Schizontocidal Activities

Cited by 40 publications

References 38 publications

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Primaquine derivatives: Modifications of the terminal amino group

Are Antimalarial Hybrid Molecules a Close Reality or a Distant Dream?

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