Synthesis and in vitro evaluation of new chloroquine-chalcone hybrids against chloroquine-resistant strain of Plasmodium falciparum

The control of malaria has been complicated with increasing resistance of malarial parasite against existing antimalarials. Herein, we report the synthesis of a new series of chloroquine-chalcone based hybrids (8-22) and their antimalarial efficacy against both chloroquine-susceptible (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Most of the compounds showed enhanced antimalarial activity as compared to chloroquine in chloroquine-resistant (K1) strain of Plasmodium falciparum. Furthermore, to unfold the mechanism of action of these synthesized hybrid molecules, we carried out hemin dependent studies, in which three compounds were found to be active.     

Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group

The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand’s Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2–12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC₅₀ = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI > 290). Some structure–activity relationships have been identified for the antimalarial activity in these abietane analogues.     

Antiplasmodial activity of new 4-aminoquinoline derivatives against chloroquine resistant strain

Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β³- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI = 5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target.     

In vitro efficiency of new acridyl derivatives against Plasmodium falciparum

A series of new 9-substituted acridyl derivatives were synthesized and their in vitro antimalarial activity was evaluated against one chloroquine-sensitive strain (3D7) and three chloroquine-resistant strains [W2 (Indochina), Bre1 (Brazil) and FCR3 (Gambia)] of Plasmodium falciparum. Some compounds inhibit the growth of malarial parasite with IC50 相似文献   

Antimalarial activity of novel pyrrolizidinyl derivatives of 4-aminoquinoline

Two pyrrolizidinylalkyl derivatives of 4-amino-7-chloroquinoline (MG2 and MG3) were prepared and tested in vitro against CQ-sensitive and CQ-resistant strains of Plasmodium falciparum and in vivo in a Plasmodium berghei mouse model of infection. Both compounds exhibited excellent activity in all tests and low toxicity against mammalian cells. Preliminary studies of the acute toxicity and of the metabolism of the most active compound MG3 indicate a promising profile as a new antimalarial drug candidate.     

Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment

Despite the urgent need for effective antimalarial drugs with novel modes of action no new chemical class of antimalarial drug has been approved for use since 1996. To address this, we have used a rational approach to investigate compounds comprising the primary benzene sulfonamide fragment as a potential new antimalarial chemotype. We report the in vitro activity against Plasmodium falciparum drug sensitive (3D7) and resistant (Dd2) parasites for a panel of fourteen primary benzene sulfonamide compounds. Our findings provide a platform to support the further evaluation of primary benzene sulfonamides as a new antimalarial chemotype, including the identification of the target of these compounds in the parasite.     

Antimalarial activity of novel 4-aminoquinolines active against drug resistant strains

In the present study we have synthesized a new class of 4-aminoquinolines and evaluated against Plasmodium falciparum in vitro (3D7-sensitive strain & K1-resistant strain) and Plasmodium yoelii in vivo (N-67 strain). Among the series, eleven compounds (5, 6, 7, 8, 9, 11, 12, 13, 14, 15 and 21) showed superior antimalarial activity against K1 strain as compared to CQ. In addition, all these analogues showed 100% suppression of parasitemia on day 4 in the in vivo mouse model against N-67 strain when administered orally. Further, biophysical studies suggest that this series of compounds act on heme polymerization target.     

Triterpenoids as inhibitors of erythrocytic and liver stages of Plasmodium infections

Bioassay-guided fractionation of the methanol extract of Momordica balsamina led to the isolation of two new cucurbitane-type triterpenoids, balsaminol F (1) and balsaminoside B (2), along with the known glycosylated cucurbitacins, cucurbita-5,24-diene-3β,23(R)-diol-7-O-β-D-glucopyranoside (3) and kuguaglycoside A (4). Compound 1 was acylated yielding two new triesters, triacetylbalsaminol F (5) and tribenzoylbalsaminol F (6). The structures were elucidated based on spectroscopic methods including 2D-NMR experiments (COSY, HMQC, HMBC and NOESY). Compounds 1-6, were evaluated for their antimalarial activity against the erythrocytic stages of the Plasmodium falciparum chloroquine-sensitive strain 3D7 and the chloroquine-resistant clone Dd2. Assessment of compounds (1-3 and 5, 6) activity against the liver stage of Plasmodium berghei was also performed, measuring the luminescence intensity in Huh-7 cells infected with a firefly luciferase-expressing P. berghei line, PbGFP-Luc(con). Active compounds were shown to inhibit the parasite's intracellular development rather than its ability to invade hepatic cells. Toxicity of compounds (1-3 and 5, 6) was assessed on the same cell line and on mouse primary hepatocytes through the fluorescence measurement of cell confluency. Furthermore, toxicity of compounds 1-6 towards human cells was also investigated in the MCF-7 breast cancer cell line, showing that they were not toxic or exhibited weak toxicity. In blood stages of P. falciparum, compounds 1-5 displayed antimalarial activity, revealing triacetylbalsaminol F (5) the highest antiplasmodial effects (IC(50) values: 0.4μM, 3D7; 0.2μM, Dd2). The highest antiplasmodial activity against the liver stages of P.berghei was also displayed by compound 5, with high inhibitory activity and no toxicity.     

Synthesis and antimalarial properties of new chloro-9H-xanthones with an aminoalkyl side chain

The synthesis and antimalarial properties of twelve new chlorinated 9H-xanthones, carrying a [2-(diethylamino)ethyl]amino group in position 1, are reported. All compounds were found to be active towards the chloroquine-susceptible and chloroquine-resistant strains 3D7 and Dd2, resp., of the protozoa parasite Plasmodium falciparum. Especially one compound, 6-chloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1k), was found to exhibit significant in vitro activity (IC50 = 3.9 microM) towards the resistant Dd2 strain.     

Synthesis and antimalarial activity of new heterocyclic hybrids based on chloroquine and thiazolidinone scaffolds

A series of new 21 chloroquine heterocyclic hybrids containing either benzylamino fragment or N-(aminoalkyl)thiazolidin-4-one moiety were synthesized and screened for their antimalarial activity against chloroquine (CQ)-sensitive 3D7 and multidrug-resistance Dd2 strains of Plasmodium falciparum. Although no compounds more active than CQ against 3D7 was found; against Dd2 strain, six compounds, four of them with benzylamino fragment, showed an excellent activity, up to 3-fold more active than CQ. Non specific cytotoxicity on J774 macrophages was observed in some compounds whereas only two of them showed liver toxicity on HepG2 cells. In addition, all active compounds inhibited the ferriprotoporphyrin IX biocrystalization process in concentrations around to CQ. In vivo preliminary results have shown that at least two compounds are as active as CQ against Plasmodium berghei ANKA.     

Design and development of novel N-(4-aminobenzoyl)- l-glutamic acid conjugated 1,3,5-triazine derivatives as Pf-DHFR inhibitor: An in-silico and in-vitro study

In the present work, a library of 120 compounds was prepared using various aliphatic and aromatic amines. Finally, 10 compounds were selected through in silico screening carrying 4-aminobenzoyl-l -glutamic acid and 1,3,5-triazine moiety. The docking results of compounds 4d16 and 4d38 revealed higher binding interaction with amino acids Asp54 (−537.96 kcal/mol) and Asp54, Phe116 (−618.22 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR inhibitors and were comparable to standard WR99210. These compounds were developed by facile and microwave-assisted synthesis via nucleophilic substitution reaction and characterized by different spectroscopic methods. In vitro antimalarial assay results also suggested that these two compounds were having higher antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain out of the ten synthesized compounds with IC₅₀ 13.25 μM and 14.72 μM, respectively. These hybrid scaffolds might be useful in the lead discovery of a new class of Pf-DHFR inhibitors.     

Novel amodiaquine congeners as potent antimalarial agents

To develop new classes of antimalarial agents, the possibility of replacing the phenolic ring of amodiaquine, tebuquine, and isoquine with other aromatic nuclei was investigated. Within a first set of pyrrole analogues, several compounds displayed high activity against both D10 (CQ-S) and W-2 (CQ-R) strains of Plasmodium falciparum. The isoquine structure was also modified by replacing the diethylamino group with more metabolically stable bicyclic moieties and by replacing the aromatic hydroxyl function with a chlorine atom. Among these compounds, two quinolizidinylmethylamino derivatives (6f and 7f) displayed high activity against both CQ-S and CQ-R strains.     

Antimicrobial effects of N-benzyloxycarbonyl-S-(2,4-dinitrophenyl) glutathione diesters against chloroquinine sensitive (NF54) and resistant (K1) strains of Plasmodium falciparum

N-Benzyloxycarbony-S-(2,4-dinitrophenyl)glutathione diesters have been investigated for antimalarial activity against chloroquinine sensitive (NF54) and resistant (K1) strains of P. falciparum. Both strains appear equally susceptible to inhibition by compounds 1–4, with an IC₅₀ ∼ 4.92–6.97 μM, consistent with the target of these compounds being the PfMRP transporter. Against the NF54 strain, diester derivatives containing ethyl side chains showed lower in vitro activity than those with methyl side chains 1–4, IC₅₀ ∼ 5.7–6.97 μM with the exception of compound 5 (IC₅₀ > 25 μM). The cytotoxicity of compounds with log P ∼ 3.9–5.8 were lower against the murine L6 cell line than compounds with a higher log P > 5.8 that were toxic. Overall the cytotoxicity of compounds 1–7 were lower against KB cells than against the L6 cell line with the exception of compound 4, which showed a higher relative toxicity.     

Synthesis, biological evaluation and mechanistic studies of totarol amino alcohol derivatives as potential antimalarial agents

Herein we report on the semisynthesis and biological evaluation of β-amino alcohol derivatives of the natural product totarol and other simple aromatic systems. All β-amino alcohol derivatives of totarol exhibited higher antiplasmodial activity than totarol [IC(50): 11.69 μM (K1, chloroquine and multi-drug resistant strain), and 11.78 μM (D10, chloroquine sensitive strain)]-12e was the most active [IC(50): 0.63 μM (K1), and 0.61 μM (D10)]. The phenyl and naphthyl β-amino alcohol derivatives were much less active than their corresponding totarol equivalents. The majority of the β-amino alcohol derivatives of totarol were more active against K1 than the D10 strains of Plasmodium falciparum, a trend similar to the inverse relationship observed with the established aryl-amino alcohol antimalarial mefloquine. Selected compounds were shown to affect erythrocyte morphology, inhibit erythrocyte invasion and trigger CQ accumulation.     

Short synthesis and antimalarial activity of fagaronine

Herein, we report a new synthesis of fagaronine 1, inspired by the synthesis reported by Luo for nornitidine. The in vitro biological activity of fagaronine against malaria on several chloroquine-sensitive and resistant Plasmodium falciparum strains was confirmed, and the selectivity index compared to mammalian cells was calculated. Fagaronine was found to have very good antimalarial activity in vivo, comparable to the activity of the reference compound chloroquine. Therefore, fagaronine appears to be a good potential lead for the design of new antimalarial molecules.     

Search for new pharmacophores for antimalarial activity. Part I: Synthesis and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides

A total of 80 new 2-methyl-6-ureido-4-quinolinamides were synthesized and evaluated for their antimalarial activity. Several analogs elicited the antimalarial effect at MIC of 0.25 mg/mL against the chlooquine-sensitive P. falciparum strain. The IC₅₀ values of the active compounds were observed to be in ng/mL range and two of the analogs have better IC₅₀ value than the standard chloroquine. In the in vivo assay against mdr CQ resistant P. yoelii N67/P. yoelii nigeriensis, however, none of the compound showed complete suppression of parasitemia on day 7. One of the compounds displayed significant antibacterial effect against several strains of bacteria and was many-fold better than the standard drug gentamicin.     

Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds

A targeted series of chalcone and dienone hybrid compounds containing aminoquinoline and nucleoside templates was synthesized and evaluated for in vitro antimalarial activity. The Cu(I)-catalyzed cycloaddition of azides and terminal alkynes was applied as the hybridization strategy. Several chalcone-chloroquinoline hybrid compounds were found to be notably active, with compound 8b the most active, exhibiting submicromolar IC(50) values against the D10, Dd2 and W2 strains of Plasmodium falciparum.     

Synthesis and evaluation of febrifugine analogues as potential antimalarial agents

Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum. Strong liver toxicity has precluded febrifugine as a potential clinical drug. In this study novel febrifugine analogues were designed and synthesized. Lower toxicity was achieved by reducing or eliminating the tendency of forming chemically reactive and toxic intermediates and metabolites. Synthesized compounds were evaluated in vitro against chloroquine sensitive (D6) and chloroquine resistant (W2) P. falciparum strains for efficacy and in freshly isolated rat hepatocytes for potential cytotoxicity. The IC(50)'s of the best compounds were superior to their parent compound febrifugine. Noticeably, these compounds were also over 100 times less toxic than febrifugine. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.     

Effects of novel triple-stage antimalarial ionic liquids on lipid membrane models

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.     

Antimalarial activity of 10-alkyl/aryl esters and -aminoethylethers of artemisinin

A series of n-alkyl/aryl esters were synthesized and their in vitro antiplasmodial activity was measured alongside that of previously synthesized aminoethylethers of artemisinin ozonides against various strains of Plasmodium falciparum. The cytotoxicity against human cell lines was also assessed. The esters were synthesized in a one-step reaction by derivatization on carbon C-10 of dihydroartemisinin. Both classes were active against both the 3D7 and K1 strains of P. falciparum, with all compounds being significantly more potent than artemether against both strains. The majority of compounds possessed potency either comparable or more than artesunate with a high degree of selectivity towards the parasitic cells. The 10α-n-propyl 11 and 10α-benzyl 18 esters were the most potent of all synthesized ozonides, possessing a moderate (∼3-fold) and significant (22- and 12-fold, respectively) potency increases against the 3D7 and K1 strains, respectively, in comparison with artesunate.