Chloroquine-resistant K1 Research Articles

Palladium-catalyzed facile synthesis of imidazo[1,2-a]pyridine-flavone hybrids and evaluation of their antiplasmodial activity

An efficient cross-coupling reaction between imidazo[1,2-a]pyridine derivatives and 6-bromoflavones has been well established. This reaction proceeds through a Palladium-catalyzed cross-coupling reaction to provide imidazo[1,2-a]pyridine-flavone hybrids in good to excellent yield. Short reaction time, high yield, and wide substrate scope are the major advantages of this method. Using SYBR Green I assay, these hybrid molecules were examined for anti-plasmodial activity against Chloroquine-sensitive 3D7 and Chloroquine-resistant K1 strains of Plasmodium falciparum. The compounds 9o {IC50s (µM) 1.983D7, 1.98K1} and 9p {IC50s (µM) 1.923D7, 5.45K1} were found to be the most potent anti-plasmodial compounds in the series. Also, all these compounds were found to be non-cytotoxic towards Vero cells with their CC50s > 100 µM. We have conducted microscopic examination experiments on compounds 9o and 9p, which resulted in a drastic impact on parasite growth of the malaria parasite. The interaction of these two potent hybrids was also examined in the binding site of wild-type Pf-DHFR-TS (Plasmodium falciparum dihydrofolate reductase-thymidylate synthase) using molecular docking studies. The computational ADME studies of the hybrid compounds confirmed their significant physicochemical, pharmacokinetic, and drug-likeness properties confirming these hybrids as a new oral antimalarial agent. As a result, these new hybrid compounds could be valuable in the creation of future antimalarial drugs.

Semi-Synthetic Analogues of Cryptolepine as a Potential Source of Sustainable Drugs for the Treatment of Malaria, Human African Trypanosomiasis, and Cancer.

The prospect of eradicating malaria continues to be challenging in the face of increasing parasite resistance to antimalarial drugs so that novel antimalarials active against asexual, sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials need to be affordable and available to those most in need and, bearing in mind climate change, should ideally be sustainable. The West African climbing shrub Cryptolepis sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid, cryptolepine (1), has been shown to have antimalarial properties, and the synthetic analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C. sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with respect to the dried roots). Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and 7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds were active against Plasmodia in vitro, but 6 showed the most selective profile with respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI = 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites IC50 = 6.13 µM, SI = 4.6. Compounds 3–6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3–6 potently inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant ovarian cancer cells. In an acute oral toxicity test in mice, 3–6 did not exhibit toxic effects at doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C. sanguinolenta may be utilized as a sustainable source of novel compounds that may lead to the development of novel agents for the treatment of malaria, African trypanosomiasis, and cancer.

A Mitochondria-Penetrating Peptide Exerts Potent Anti-Plasmodium Activity and Localizes at Parasites' Mitochondria.

Mitochondria are considered a novel drug target as they play a key role in energy production and programmed cell death of eukaryotic cells. The mitochondria of malaria parasites differ from those of their vertebrate hosts, contributing to the drug selectivity and the development of antimalarial drugs. (Fxr)3, a mitochondria-penetrating peptide or MPP, entered malaria-infected red cells without disrupting the membrane and subsequently killed the blood stage of P. falciparum parasites. The effects were more potent on the late stages than on the younger stages. Confocal microscopy showed that the (Fxr)3 intensely localized at the parasite mitochondria. (Fxr)3 highly affected both the lab-strain, chloroquine-resistant K1, and freshly isolated malaria parasites. (Fxr)3 (1 ng/mL to 10 μg/mL) was rarely toxic towards various mammalian cells, i.e., mouse fibroblasts (L929), human leukocytes and erythrocytes. At a thousand times higher concentration (100 μg/mL) than that of the antimalarial activity, cytotoxicity and hemolytic activity of (Fxr)3 were observed. Compared with the known antimalarial drug, atovaquone, (Fxr)3 exhibited more rapid killing activity. This is the first report on antimalarial activity of (Fxr)3, showing localization at parasites’ mitochondria.

Synthesis and Antimalarial Activity of 4-Methylaminoquinoline Compounds against Drug-Resistant Parasite.

A series of novel 4-aminoquinoline analogues bearing a methyl group at 4-aminoquinoline moiety were synthesized via a new and robust synthetic route comprising in situtert-butoxycarbonyl (Boc) deprotection–methylation cascade resulting in the corresponding N-methylated secondary amine using Red-Al and an efficient microwave-assisted strategy for the fusion of N-methylated secondary amine with 4-chloroquinoline nucleus to access the series of novel 4-N-methylaminoquinoline analogues. The new series of compounds were evaluated for their antimalarial activity in in vitro and in vivo models. Among 21 tested compounds, 9a–i have shown a half-maximal inhibitory concentration (IC50) value less than 0.5 μM (i.e., <500 nM) against both chloroquine-sensitive strain 3D7 and chloroquine-resistant strain K1 of Plasmodium falciparum with acceptable cytotoxicity. Based on the in vitro antimalarial activity, selected compounds were screened for their in vivo antimalarial activity against Plasmodium yoelii nigeriensis (a multidrug-resistant) parasite in Swiss mice. Most of the compounds have shown significant inhibition on day 4 post infection at the oral dose of 100 mg/kg. Compound 9a has shown 100% parasite inhibition on day 4, and out of five treated mice, two were cured till the end of the experiment. The present study suggests that 4-methylamino substitution is well tolerated for the antiplasmodial activity with reduced toxicity and therefore will be highly useful for the discovery of a new antimalarial agent against drug-resistant malaria.

Metacytofilin has potent anti-malarial activity.

Metacytofilin (MCF) was isolated from the fungus Metarhizium sp. TA2759. Although MCF possesses anti-Toxoplasma activity, the effects of this compound against other parasites are unknown. Here, we evaluated the in vitro anti-malarial activity of MCF against the 3D7 strain and the chloroquine-resistant K1 strain of Plasmodium falciparum. The half maximal inhibitory concentrations (IC50) of MCF against the 3D7 and K-1 strains following culture for 48h were 666nM and 605nM, respectively. Artemisinin was more potent than MCF against both strains (3D7 IC50: 17.4nM; K-1 IC50: 18.3nM), while chloroquine was ineffective against the chloroquine-resistant strain (3D7 IC50: 39.1nM; K-1 IC50: 1.62μM). MCF affected the ring stage of the parasites, resulting in their death as shown by spots within red blood cells. MCF also inhibited parasite growth following culture for 72h (3D7 IC50, 285nM). Four optical isomers of cyclo[Leu-Phe]-diketopiperazine derivatives with modified methoxy and/or hydroxyl groups lost anti-malarial activity, suggesting that the spatial positions of the methoxy and hydroxyl groups in MCF play an important role in its anti-malarial effects. Together, these data suggest that MCF may represent a promising lead compound for treatment of drug-resistant malarial parasites.

Discovery of a potent histone deacetylase (HDAC) 3/6 selective dual inhibitor

Herein, we report the discovery of a dual histone deacetylase inhibitor displaying a unique HDAC3/6 selectivity profile. An initial strategy to merge two epigenetic pharmacophores resulted in the discovery of potent HDAC6 inhibitors with selectivity over HDAC1. Screening in an HDAC panel revealed additional low nanomolar inhibition only against HDAC3. Low micromolar antiproliferative activities against two breast cancer and four hematological cancer cell lines was supported by pharmacodynamic studies on a preferred molecule, 24c, substantiating the HDAC inhibitory profile in cells. Apoptosis was identified as one of the main cell death pathways. Modelling studies of 24c against HDAC1,2,3 and 6 further provided insights on the orientation of specific residues relevant to compound potency, explaining the observed HDAC3/6 selectivity. A subset of the compounds also exhibited good antimalarial activities, particularly against the chloroquine-resistant strain K1 of P.falciparum. In vitro studies revealed a favourable DMPK profile warranting further investigation of the therapeutic potential of these compounds.

Evaluation of PTA-derived ruthenium(II) and iridium(III) quinoline complexes against chloroquine-sensitive and resistant strains of the Plasmodium falciparum malaria parasite

Cationic 1,3,5‑triaza‑phosphaadamantane (PTA) quinoline ruthenium(II) and iridium(III) complexes were successfully synthesized and characterized using standard spectroscopic and analytical techniques. The complexes were evaluated for their in vitro antiplasmodial activities against the chloroquine-sensitive (CQS) NF54 and chloroquine-resistant (CQR) K1 strains of the Plasmodium falciparum species of the malaria parasite and were found to exhibit good activities in the sensitive strain but moderate activities in the resistant strain, suggesting a resistance mechanism similar to chloroquine (CQ). Selected samples were screened for their ability to inhibit synthetic haemozoin formation and were found to be inhibitors with similar activity to CQ. The complexes also exhibit moderate to low cytotoxicity when evaluated against the Chinese Hamster Ovarian (CHO) cell-line in vitro, suggesting selectivity towards the malaria parasite rather than mammalian cells.

Synthesis, antimalarial activities and cytotoxicities of amino-artemisinin-1,2-disubstituted ferrocene hybrids

Artemisinin-ferrocene conjugates incorporating a 1,2-disubstituted ferrocene analogous to that embedded in ferroquine but attached via a piperazine linker to C10 of the artemisinin were prepared from the piperazine artemisinin derivative, and activities were evaluated against asexual blood stages of chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf). The most active was the morpholino derivative 5 with IC50 of 0.86 nM against Pf K1 and 1.4 nM against Pf W2. The resistance indices were superior to those of current clinical artemisinins. Notably, the compounds were active against Pf NF54 early and late blood stage gametocytes – these exerted >86% inhibition at 1 µM against both stages; they are thus appreciably more active than methylene blue (∼57% inhibition at 1 µM) against late stage gametocytes. The data portends transmission blocking activity. Cytotoxicity was determined against human embryonic kidney cells (Hek293), while human malignant melanoma cells (A375) were used to assess their antitumor activity.

Study of the antimalarial activity of 4-aminoquinoline compounds against chloroquine-sensitive and chloroquine-resistant parasite strains

This study is concerned with identifying features of 4-aminoquinoline scaffolds that can help pinpoint characteristics that enhance activity against chloroquine-resistant parasites. Statistically valid predictive models are reported for a series of 4-aminoquinoline analogues that are active against chloroquine-sensitive (NF54) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Quantitative structure activity relationship techniques, based on statistical and machine learning methods such as multiple linear regression and partial least squares, were used with a novel pruning method for the selection of descriptors to develop robust models for both strains. Inspection of the dominant descriptors supports the hypothesis that chemical features that enable accumulation in the food vacuole of the parasite are key determinants of activity against both strains. The hydrophilic properties of the compounds were found to be crucial in predicting activity against the chloroquine-sensitive NF54 parasite strain, but not in the case of the chloroquine-resistant K1 strain, in line with previous studies. Additionally, the models suggest that ‘softer’ compounds tend to have improved activity for both strains than do ‘harder’ ones. The internally and externally validated models reported here should also prove useful in the future screening of potential antimalarial compounds for targeting chloroquine-resistant strains.Graphical Predictive models reveal linear relationships for activity of 4-aminoquinoline analogues active against chloroquine-sensitive strains of Plasmodium falciparum

Pharmacological Investigation of Solanum incanum against P. falciparum, L. infantum, T. cruzi and T. brucei : A Role of Antioxidant Effect and Clinical Overview

The in vitro antiprotozoal and cytotoxic activity of the Solanum incanum leaves and fruit extract of Albaha region was assessed against Plasmodium falciparum (chloroquine resistant K1 strain), Leishmania infantum, two Trypanosoma (T. cruzi and T. brucei) and MRC-5 cell-lines respectively. Additionally, ethnomedicinal studies by survey and interview, antioxidant potential by DPPH assay was studied for Solanum incanum. Results indicated that the S. incanum fruit was inactive (IC50: &gt;64 µg/mL) against P.falcipuram but leaves had shown low activity (IC50: 47 µg/mL), against L.infantum both fruit (IC50: 27.3 µg/mL) and leaves (IC50: 27.3 µg/mL) had good activity, against T.brucei both fruit (IC50: 34.1 µg/mL) and leaves (IC50: 32.7 µg/mL) had moderate activity. S incanum fruits (IC50: 9.3 µg/mL) had pronounced activity against T. cruzi but leaves (IC50: 6.0 µg/mL) had pronounced activity against T .cruzi with selectivity index &gt; 1. Solanum incanum fruits had stronger antioxidant activity (IC50: 98.7 µg/mL ) than leaves (IC50 : 293.2 µg/mL) but both fruit and leaves had lower antioxidant activity than standards (Ascorbic acid IC50: 19.1 µg/mL; Trolox IC50: 19.5 µg/mL). Our results demonstrate that S incanum leaves has promising activity against T .cruzi possibly active constituents like flavonoid, solasonine and solamargine are contributing for this effect. Furthermore previous reports demonstrate that T .cruzi infection is inhibited by antioxidant effects through NRF2 upregulation, possibly our extracts inhibited T .cruzi through antioxidant pathway.

Synthesis of Cyclic Peptides as Potential Anti-Malarials.

The results from the synthesis of peptides by Fmoc/SPPS on a 2-CTC resin and then lactamization in solution or solid phase for the preparation of cyclopeptides are presented. Both procedures allow the synthesis of the desired compounds in good to very good yield and with high cyclization efficiency for on-resin macrocyclization. In addition, the activities of the corresponding cyclopeptides against the chloroquine-resistant K1 strain of Plasmodium falciparum were evaluated. Cyclo-Cys(Trt)-Gly-Thr( tBu)-Gly-Cys(Trt)-Gly showed potent in vitro and selective activity against this parasite, EC50 = 28 nM.

Modeling and synthesis of antiplasmodial chromones, chromanones and chalcones based on natural products of Kenya

Scolastica M, Ndakala AJ, Derese S. 2018. Modeling and synthesis of antiplasmodial chromones, chromanones and chalcones based on natural products of Kenya. Biofarmasi J Nat Prod Biochem 16: 8-21. Despite numerous research that has been done on plants of Kenya resulting in the isolation of thousands of natural products, data on these natural products are not systematically organized in a readily accessible form. This has urged the construction of a web-based database of natural products of Kenya. The database is named Mitishamba and is hosted at http://mitishamba.uonbi.ac.ke. The Mitishamba database was queried for chromones, chromanones, and chalcones that were subjected to structure-based drug design using Fred (OpenEye) docking utility program with 1TV5 PDB structure of the PfDHODH receptor to identify complex of ligands that bind with the active site. Ligand-based drug design (Shape and electrostatics comparison) was also done on the ligands against query A77 1726 (38) (the ligand that co-crystallized with PfDHODH receptor) using ROCS and EON programs, respectively, of OpenEye suite. There was a substantial similarity among the top performing ligands in the docking studies with shape and electrostatic comparison that led to the identification of compounds of interest which were targeted for synthesis and antiplasmodial assay. In this study, a chromanone (7-hydroxy-2-(4-methoxyphenyl) chroman-4-one (48)) and two intermediate chalcones (2',4'-dihydroxy-4-methoxychalcone (45) and 2’,4’-dihydroxy-4-chlorochalcone (47)), were synthesized and subjected to antiplasmodial assay. Among these substances, 45 showed vigorous activity, whereas 47 and 48 had moderate activity against the chloroquine resistant K1 strain of P. falciparum with IC50 values of 4.56±1.66, 17.62 ± 5.94 and 18.01 ±1.66 µg/ml, respectively. Since the synthesized compounds showed antiplasmodial potential, there is a need for further computational refinement of these compounds to optimize their antiplasmodial activity.

Synthesis, in vitro antimalarial activities and cytotoxicities of amino-artemisinin-ferrocene derivatives

Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC50 values of 2.79 nM against Pf K1 and 3.2 nM against Pf W2. Overall the resistance indices indicate that the compounds have a low potential for cross resistance. Cytotoxicities were determined with Hek293 human embryonic kidney cells and activities against proliferating cells were assessed against A375 human malignant melanoma cells. The selectivity indices of the amino-artemisinin ferrocene derivatives indicate there is overall an appreciably higher selectivity towards the malaria parasite than mammalian cells.

Synthesis and antimalarial activity of 3′-trifluoromethylated 1,2,4-trioxolanes and 1,2,4,5-tetraoxane based on deoxycholic acid

A series of new steroidal peroxides – 3′-trifluoromethylated 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes based on deoxycholic acid were prepared via the reactions of the Griesbaum coozonolysis and peroxycondensation, respectively. 1,2,4-Trioxolanes were synthesized by the interaction of methyl O-methyl-3-oximino-12α-acetoxy-deoxycholate with CF3C(O)CH3 or CF3C(O)Ph and O3 as the mixtures of four possible stereoisomers at ratios of 1:2:2:1 and in yields of 50% and 38%, respectively. The major diastereomer of methyl 12α-acetoxy-5β-cholan-24-oate-3-spiro-5′-(3′-methyl-3′-trifluoromethyl-1′,2′,4′-trioxolane) was isolated via crystallization of a mixture of stereoisomers from hexane and its (3S,3′R)-configuration was determined using X-ray crystallographic analysis. Peroxycondensation of methyl 3-bishydroperoxy-12α-acetoxy-deoxycholate with CF3C(O)CH3 or acetone led to 1,2,4,5-tetraoxanes in yields of 44% and 37%, respectively. Antimalarial activity of these new steroidal peroxides was evaluated in vitro against the chloroquine-sensitive (CQS) T96 and chloroquine-resistant (CQR) K1 strains of Plasmodium falciparum. Deoxycholic acid 3′-trifluoromethylated 1,2,4,5-tetraoxane demonstrated a good IC50 value against CQR-strain (IC50 (K1) = 7.6 nM) of P. falciparum. Tetraoxane with the acetone subunit demonstrated the best results among all tested peroxides with an IC50 value of 3 nM against the CQ-resistant K1 strain. In general, 1,2,4-trioxolanes of deoxycholic acid are less active than 1,2,4,5-tetraoxanes.

Cinnamoylated chloroquine analogues: A new structural class of antimalarial agents

A novel series of cinnamoylated chloroquine hybrid analogues were synthesized and evaluated as antimalarial agents. The trans cinnamic acid derivatives (3–8) were synthesized by utilizing substituted aldehydes and malanoic acid in DMF catalysed by DABCO. The final cinnamoylated chloroquine analogues (9–14) were synthesized by utilizing DCC coupling reagent. The amido chloroquine (17) was prepared from acid (16) and compound 2 in benzene using SOCl2 as chlorinating agent. The corresponding ester (15) was prepared from 2-hydroxy acetophenone and 2-bromoacetates in actonitrile in presence of K2CO3 as base followed by basic hydrolysis. The preparation of amide based chloroquine-chalcone analogues (18–22), were obtained by the combination of amido chloroquine (17) and aldehydes in 10% aq. KOH in methanol at room temperature. Further we prepared epichlorohydrin based chloroquine-chalcone analogues (25–28), by reacting the epoxide (24a, 24b and 24c) with 2 and methelenedioxy aniline. In vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant strain K1 of P. falciparum and in vitro cytotoxicity of compounds using VERO cell line was carried out. The synthesized molecules showed significant in vitro antimalarial activity especially against CQ resistant strain (K1). Among tested compounds, 13, 9 and 10 were found to be the most potent compounds of the series with IC50 value of 44.06, 48.04 and 59.37 nM against chloroquine resistant K1 strain.

Antimalarial and Antiproliferative Cassane Diterpenes of Caesalpinia sappan.

Bioassay-guided fractionation of a methanol extract of the seeds of Caesalpinia sappan led to the isolation of 12 new cassane-type diterpenes, caesalsappanins A-L (1-12). Their structures were elucidated on the basis of NMR and HRESIMS analysis, and the absolute configuration of compound 1 was determined by single-crystal X-ray crystallography. All isolated compounds were tested against a chloroquine-resistant Plasmodium falciparum strain for antiplasmodial activities and against a small panel of human cancer cell lines for antiproliferative activities. Compounds 7 and 8 displayed antimalarial activity against the chloroquine-resistant K1 strain of P. falciparum with IC50 values of 0.78 and 0.52 μM and selectivity indices of 17.6 and 16.4, respectively. Compound 10 showed antiproliferative activity against the KB cancer cell line with an IC50 value of 7.4 μM.

Synthesis of isocryptolepine analogues and their structure–activity relationship studies as antiplasmodial and antiproliferative agents

Novel isocryptolepine analogues have been conveniently synthesized and evaluated for antimalarial and antiproliferative activities. We have found 3-fluoro-8-bromo-isocryptolepine (1n) to have the highest activities against chloroquine-resistant K1, chloroquine-sensitive 3D7, and chloroquine- and mefloquine-resistant SKF58 and SRIV35 strains. Several fluorine-substituted analogues (1b, 1n, and 1q) also showed excellent selectivities while maintaining good to excellent activities against all four Plasmodium falciparum strains. Additionally, antiproliferative properties of isocryptolepine derivatives against HepG2, HuCCA-1, MOLT-3 and A549 cancer cell lines are reported for the first time in this study. 2-Chloroisocryptolepine (1c) and benzo-fused-2-chloroisocryptolepine (1i) showed significant bioactivities whereas several novel fluorinated compounds and 2-chloro-8-bromoisocryptolepine (1f) displayed excellent selectivities.

Medicinal chemistry discoveries among 1,3,5-triazines: recent advances (2000-2013) as antimicrobial, anti-TB, anti-HIV and antimalarials.

The chemistry and an extensive spectrum of biological activities of s-triazines have been examined since several decades and this heterocyclic core has received emerging consensus. This article aims to summarize recent advances (2000-2013) made towards the discovery of antimicrobial, antituberculosis, anti-HIV and antimalarial agents holding 1,3,5-triazine ring as a nucleus with the substitution of several types of nucleophiles. Molecular patterns associated with particular potency have been identified targeting several Gram-positive and Gram-negative bacteria and some fungal species, mycobacterium tuberculosis H37Rv, HIV type I and HIV type II, particularly, HIV-1I IIB and HIV- 1ROD strains as well as a variety of P. falciparum malarial strains as chloroquine-resistant K1, chloroquine-susceptible NF54, chloroquine-sensitive 3D7, P. falciparum (D6 clone), P. falciparum (W2 clone), cycloguanil-resistant FCR-3, chloroquine sensitive RKL2. The report will be of considerable interest to gain useful information for the furtherance of drug discovery with extended 1,3,5-triazine designs.

Design and Synthesis of a New Class of 4‐Aminoquinolinyl‐ and 9‐Anilinoacridinyl Schiff Base Hydrazones as Potent Antimalarial Agents

A series of novel 4-aminoquinolinyl and 9-anilinoacridinyl Schiff base hydrazones have been synthesized and evaluated for their antimalarial activity. All compounds were evaluated in vitro for their antimalarial activity against chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain of Plasmodium falciparum and for cytotoxicity toward Vero cells. Compounds 17, 20, and 21 displayed good activity against the 3D7 strain with IC50 values ranging from 19.69 to 25.38nm. Moreover, compounds 16, 17, 21, 24, 32, and 33 exhibited excellent activities (21.64-54.26nm) against K1 strain and several compounds displayed β-hematin inhibitory activity, suggesting that they act on the heme crystallization process such as CQ. Compounds were also found to be non-toxic with good selectivity index.

Synthesis and evaluation of new diaryl ether and quinoline hybrids as potential antiplasmodial and antimicrobial agents

Synthesis and bioevaluation of new diaryl ether hybridized quinoline derivatives as antiplasmodial, antibacterial and antifungal agents is reported. It was encouraging to discover that several compounds displayed 2–3 folds better efficacy than chloroquine in chloroquine-resistant K1 strain of Plasmodium falciparum. Further, a few members of the library displayed good antibacterial efficacy against gram positive strains of bacteria but none of the compounds displayed any significant antifungal activity.