Antiplasmodial activity of novel keto-enamine chalcone-chloroquine based hybrid pharmacophores

Sashidhara, Koneni V.; Kumar, M.; Modukuri, Ram K.; Srivastava, Rajeev; Soni, Awakash; Srivastava, Kumkum; Singh, Sweta; Saxena, Jitendra Kumar; Gauniyal, Harsh M.; Puri, Sunil K.

doi:10.1016/j.bmc.2012.03.011

Cited by 55 publications

(19 citation statements)

References 31 publications

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“…(24,25). A series of novel ketoenamine chalcone-chloroquine-based hybrids were synthesized, and compounds 25 and 27 each showed 99.9% in vivo suppression of parasitemia at a dosage of 100 mg/ kg/day by the oral route (26). A series of novel 4-anilinoquinoline Mannich base molecules were synthesized, and the in vivo inhibition of Plasmodium yoelii N67 in Swiss mice by compound BM-1 [4-(7-chloroquinolin-4-ylamino)-2-morpholin-4-ylmethylphenol] at a dosage of 500 mg/kg by the oral route was 100% (27).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

Zhao

et al. 2014

Antimicrob Agents Chemother

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dArtemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (LE) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. Their physical and chemical stabilities were also evaluated. Furthermore, the in vivo antimalarial activities of the lipid emulsions developed were tested in Plasmodium berghei-infected mice. Artemether, lumefantrine, or artemether in combination with lumefantrine was encapsulated in an oil phase, and the in vivo performance was assessed by comparison with artesunate for injection. It was found that the lumefantrine lipid emulsion (LUM-LE) and artemether-lumefantrine lipid emulsion (ARM-LUM-LE-3) (1:6) began to decrease the parasitemia levels after only 3 days, and the parasitemia inhibition was 90% at doses of 0.32 and 0.27 mg/kg, respectively, with immediate antimalarial effects greater than those of the positive-control group and constant antimalarial effects over 30 days. LUM-LE and ARM-LUM-LE-3 demonstrated the best performance in terms of chemical and physical stabilities and antiplasmodial efficacy, with a mean particle size of 150 nm, and they have many favorable properties for parenteral administration, such as biocompatibility, physical stability, and ease of preparation. Malaria is one of the most significant causes of morbidity and death worldwide. Every year, nearly one million deaths result from malaria infection, with about 85% occurring among children under 5 years of age. Indeed, one patient dies from malaria every 36 s (1).Artemisinin and its derivatives are the most important antimalarial drugs; the chemical structures of the four artemisinin compounds and lumefantrine (also known as benflumetol) are presented in Fig. 1. Artemisinin is an effective antimalarial drug isolated from the Chinese herbal medicine Artemisia annua L. It has a special sesquiterpene lactone with a peroxy group. In malaria parasites, artemisinin can be activated by intraparasitic heme iron, which catalyzes cleavage of the endoperoxide (2). Due to its unique structure and antimalarial mechanism, artemisinin has excellent antimalarial activity with low toxicity; therefore, artemisinin-based combination therapy (ACT) is recommended as the first-line strategy to treat malaria (3). After the introduction of ACT interventions, morbidity and mortality rates associated with malaria were decreased in several parts of the world (4). However, antimalarial resistance would probably be increased after longterm application of artemisinin alone. WHO reformed the malaria treatment policy in February 2004, proposing to stop the use of single antimalarial drugs (e.g., artemisinin and quinine) and promoting the use of ACTs. Recently, combination therapies such as artemether in co...

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Section: Discussionmentioning

confidence: 99%

Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

Zhao

et al. 2014

Antimicrob Agents Chemother

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“…Hybrids with a linker chain length of greater than three were found to be less potent than chloroquine. The members of the O'Neill group, which worked on synthetic 1,2,4-trioxolaquines (91), and several others (62,92), have reported similar results. Therefore, the length and nature of the linker exert a strong influence on the antimalarial efficacy of the conjugates.…”

Section: Linker Selectionmentioning

confidence: 70%

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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“…Seven of them 62a ‐ g (IC 50 : 3.36‐9.75 nM) with IC 50 less than 10 nM against CQS 3D7 strain also showed great potency (suppressed ≥99.5% parasitaemia at day 4 by PO at dose of 100 mg/kg/day) in N‐67 P yoelii infected Swiss mice model. The most active hybrids 62f , g exhibited 99.9% suppression on day 4 compared to 99% suppression displayed by CQ (at 20 mg/kg/day dose), but the curative effect (no recrudescence, cured mice) was not obtained at the tested dose …”

Section: Quinoline Hybridized With Novel Antimalarial Pharmacophores mentioning

confidence: 86%

“…The antiplasmodial activity of quinoline‐chalcone hybrids 62 (IC 50 : 3.36‐42.86 nM) was higher than that of 63 (IC 50 : 80.01‐379.82 nM) against CQS 3D7 strain, implying the linker between quinoline and chalcone moieties influenced the activity remarkably . Seven of them 62a ‐ g (IC 50 : 3.36‐9.75 nM) with IC 50 less than 10 nM against CQS 3D7 strain also showed great potency (suppressed ≥99.5% parasitaemia at day 4 by PO at dose of 100 mg/kg/day) in N‐67 P yoelii infected Swiss mice model.…”

Section: Quinoline Hybridized With Novel Antimalarial Pharmacophores 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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Antiplasmodial activity of novel keto-enamine chalcone-chloroquine based hybrid pharmacophores

Cited by 55 publications

References 31 publications

Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

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

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

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