Property-based design and synthesis of new chloroquine hybrids via simple incorporation of 2-imino-thiazolidin-4-one or 1h-pyrrol-2, 5-dione fragments on the 4-amino-7-chloroquinoline side chain (original) (raw)
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Synthesis and antimalarial activity of side chain modified 4-aminoquinoline derivatives
2007
Contents of Supporting Information Contents Page No. General experimental section S2 General synthetic procedure for compounds 4-33 S2 Experimental details of IR, 1 H-NMR and MASS spectral data for synthesized compounds 4-33 S5 Elemental analyses of derivatives 4-33 S16 Biological and Biophysical studies S17 S-2 General experimental section. Meting points (mp) were determined on a complab melting point apparatus and are uncorrected. IR spectra (cm-1) were recorded on Perkin-Elmer 621 spectrometer using the KBr disc technique. The 1 H-NMR and 13 C MNR spectra were recorded on a DPX-200 MHz Bruker FT-NMR spectrometer using CDCl 3 and DMSO-d 6 as solvent. Tetramethylsilane (δ 0.0 ppm) was used as an internal standard. Fast Atom Bombardment Mass Spectra (FABMS) were obtained on Jeol (Japan)/SX-102 spectrometer using glycerol or m-nitrobenzyl alcohol as matrix. Elemental analysis was performed on a Perkin-Elmer 2400 C,H,N analyzer and values were within the acceptable limits of the calculated values. The progress of the reaction was monitored on readymade TLC silica gel plates (Merck) using chloroform-methanol (9:1) as a solvent system. Iodine was used as developing agent or by spraying with Dragendorff's reagent. Chromatographic purification was performed over silica gel (100-200 mesh). All chemicals and reagents were obtained from Aldrich (USA), Lancaster (UK) or Spectrochem Pvt.Ltd (India) and were used without further purification. General synthetic procedure for compounds 4-33 General synthetic procedure for 3-[(7-Chloroquinolin-4-ylamino)-alkyl]thiazolidin-4-one (4, 14, 24) The appropriate amine (1.0 mmol), aldehyde (2.0 mmol) and mercaptoacetic acid (3.0 mmol) in 20 ml dry toluene was heated to reflux for 12-16 h. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure and the residue was taken up in chloroform and washed with 5% aq. sodium hydrogen carbonate and then finally with brine solution. The organic phase was then dried over sodium sulfate, the filtrate was concentrated to dryness under S-3 reduced pressure and the crude product was purified by column chromatography on silica gel using chloroform-methanol. General synthetic procedure for for 3-[(7-Chloroquinolin-4-ylamino)-alkyl]-2-(substituted)-thiazolidin-4-one (5, 6, 15, 16, 25, 26) The appropriate amine (1.0 mmol) and aldehyde (2.0 mmol) were stirred in THF under ice-cold condition for 5 min, followed by addition of mercaptoacetic acid (3.0 mmol). After 5 min DCC (1.2 mmol) was added to the reaction mixture at 0°C and the reaction mixture was stirred for an additional 50 min at room temprature. DCU was removed by filtration and the filtrate was concentrated to dryness under reduced pressure and the residue was taken up in chloroform. The organic layer was successively washed with 5% aq. sodium hydrogen carbonate and then finally with brine solution. The organic layer was dried over sodium sulphate and solvent was removed under reduced pressure to get a crude product that was purified by column chromatography on silica gel using chloroform-methanol. General synthetic procedure for 3-[(7-Chloroquinolin-4-ylamino)-alkyl]-5-methylthiazolidin-4-one (7, 17, 27) The appropriate amine (1.0 mmol), aldehyde (2.0 mmol) and thiolactic acid (3.0 mmol) in 20 mL dry toluene was heated to reflux for 14-16 h. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure and the residue was taken up in chloroform and washed with 5% aq. sodium hydrogen carbonate and then finally with brine solution. The organic phase was then dried over sodium sulfate, the filtrate was concentrated to dryness under reduced pressure and the crude product was purified by column chromatography on silica gel using chloroform-methanol.
Synthesis and Evaluation of 7-Substituted 4-Aminoquinoline Analogues for Antimalarial Activity
Journal of Medicinal Chemistry, 2011
We previously reported that substituted 4-aminoquinolines with a phenylether substituent at the 7position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine's alkyl substituents exhibited potent antimalarial activity against the multi-drug resistant strain P. falciparum W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogs, in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquineresistant K1 and cytotoxicity mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1strain good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study.
2012
A new series of quinoline analogs have been synthesized and found active against P. falciparum in vitro and P. yoelli in vivo. Compounds 8, 10 and 11 exhibited superior in vitro activity compared to chloroquine. Selected compounds 8, 10 and 11 exhibited significant suppression of parasitaemia in vivo assay. These analogs form a complex with hematin and inhibit the β-hematin formation, suggesting that this class of compounds act on a heme polymerization target. Further this study confirms that quinoline ring nitrogen is essential for both transportation of the molecule across the membrane as well as for tight binding to hematin.
Synthesis and Evaluation of Antimalarial Properties of Novel 4-Aminoquinoline Hybrid Compounds
Chemical Biology & Drug Design, 2014
Pharmacophore hybridization has recently been employed in the search for antimalarial lead compounds. This approach chemically links two pharmacophores, each with their own antimalarial activity and ideally with different modes of action, into a single hybrid molecule with the goal to improve therapeutic properties. In this paper we report the synthesis of novel 7-chloro-4-aminoquinoline:primary sulfonamide hybrid compounds. The chlorinated 4aminoquinoline scaffold is the core structure of chloroquine, an established antimalarial drug, while the primary sulfonamide functional group has a proven track record of efficacy and safety in many clinically used drugs and was recently shown to exhibit some antimalarial activity. The activity of the hybrid compounds was determined against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. While the hybrid compounds had lower antimalarial activity when compared to chloroquine, they demonstrated a number of interesting structure-activity relationship (SAR) trends including the potential to overcome the resistance profile of chloroquine.
Antimalarial activity of novel pyrrolizidinyl derivatives of 4-aminoquinoline
Bioorganic & Medicinal Chemistry Letters, 2008
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.
Bioorganic & Medicinal Chemistry, 2011
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.
Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities
Bioorganic & Medicinal Chemistry Letters, 2005
A simple two-step synthesis method was used to make 51 B-ring-substituted 4-hydroxyquinolines allowing analysis of the effect of ring substitutions on inhibition of growth of chloroquine sensitive and resistant strains of Plasmodium falciparum, the dominant cause of malaria morbidity. Substituted quinoline rings other than the 7-chloroquinoline ring found in chloroquine were found to have significant activity against the drug-resistant strain of P. falciparum W2.
European Journal of Medicinal Chemistry, 2018
A series of novel molecular hybrids based on 4-aminoquinoline-pyrimidine were synthesized and examined for their antimalarial activity. Most of the compounds were found to have potent in vitro antimalarial activity against both CQ-sensitive D6 and CQ-resistant W2 strains of P. falciparum. The active compounds have no considerable cytotoxicity against the mammalian VERO cell lines. Twenty three compounds displayed better antimalarial activity against CQ-resistant strain W2 with IC 50 values in the range 0.0189-0.945 µM, when compared with standard drug chloroquine. The best active compound 7d was studied for heme binding so as to find the primary mode of action of these hybrid molecules. Compound 7d was found to form a stable 1:1 complex with hematin as determined by its Job's plot which suggests that heme may be a probable target of these molecules. Docking studies performed with Pf-DHFR exhibited good binding interactions in the active site. The pharmacokinetic properties of some active compounds were also analysed using ADMET prediction.
Journal of Chemistry
Quinoline heterocycle is a useful scaffold to develop bioactive molecules used as anticancer, antimalaria, and antimicrobials. Inspired by their numerous biological activities, an attempt was made to synthesize a series of novel 7-chloroquinoline derivatives, including 2,7-dichloroquinoline-3-carbonitrile (5), 2,7-dichloroquinoline-3-carboxamide (6), 7-chloro-2-methoxyquinoline-3-carbaldehyde (7), 7-chloro-2-ethoxyquinoline-3-carbaldehyde (8), and 2-chloroquinoline-3-carbonitrile (12) by the application of Vilsmeier–Haack reaction and aromatic nucleophilic substitution of 2,7-dichloroquinoline-3-carbaldehyde. The carbaldehyde functional group was transformed into nitriles using POCl3 and NaN3, which was subsequently converted to amide using CH3CO2H and H2SO4. The compounds synthesized were screened for their antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pyogenes. Compounds 6 and 8 showed good activity against E. col...