53186-45-1Relevant articles and documents
Binding to deoxyribonucleic acid and inhibition of ribonucleic acid polymerase by analogs of chloroquine.
Burckhalter et al.
, p. 856,861 (1974)
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Targeting Asexual and Sexual Blood Stages of the Human Malaria Parasite P. falciparum with 7-Chloroquinoline-Based 1,2,3-Triazoles
Wadi, Ishan,Prasad, Davinder,Batra, Neha,Srivastava, Kumkum,Anvikar, Anupkumar R.,Valecha, Neena,Nath, Mahendra
, p. 484 - 493 (2019)
Novel 4-amino-7-chloroquinoline-based 1,2,3-triazole hybrids were synthesised in good yields by CuI-catalysed Huisgen 1,3-dipolar cycloaddition reactions of 2-azido-N-(7-chloroquinolin-4-ylaminoalkyl)acetamides with various terminal alkynes. Th
Application of multicomponent reactions to antimalarial drug discovery. Part 2: New antiplasmodial and antitrypanosomal 4-aminoquinoline γ- and δ-lactams via a 'catch and release' protocol
Musonda, Chitalu C.,Gut, Jiri,Rosenthal, Philip J.,Yardley, Vanessa,Carvalho de Souza, Renata C.,Chibale, Kelly
, p. 5605 - 5615 (2006)
A parallel synthesis of a new series of 4-aminoquinoline γ- and δ-lactams synthesized via the Ugi 3-component 4-centre multicomponent reaction is described. The basicity of the quinoline nitrogen was exploited in the purification of compounds via a 'catch and release' protocol. Yields ranging from 60% to 77% and purities as high as 96% were obtained. Compound 29, the most active against a chloroquine-resistant W2 strain of Plasmodium falciparum with an IC50 of 0.096 μM, also inhibited recombinant falcipain-2 in vitro (IC50 = 17.6 μM). Compound 17 inhibited the growth of Trypanosoma brucei with an ED50 of 1.44 μM whilst exhibiting a favourable therapeutic index of 409 against a human KB cell line.
Antimalarial and anti-inflammatory activities of new chloroquine and primaquine hybrids: Targeting the blockade of malaria parasite transmission
Boechat, Nubia,Carvalho, Rita C.C.,Ferreira, Maria de Lourdes G.,Coutinho, Julia Penna,Sa, Paula M.,Seito, Leonardo N.,Rosas, Elaine C.,Krettli, Antoniana U.,Bastos, Monica M.,Pinheiro, Luiz C.S.
, (2020)
Malaria is a disease that requires new drugs not only to fight Plasmodium but also to reduce symptoms of infection such as fever and inflammation. A series of 21 hybrid compounds were designed from chloroquine (CQ) and primaquine (PQ) linked to the pharmacophoric group present in phenylacetic anti-inflammatory drugs. These compounds were designed to have dual activity: namely, to be capable of killing Plasmodium and still act on the inflammatory process caused by malaria infection. The compounds were assayed with nine different biological methods. The carbonylated CQ derivative 6 (n = 3; R1 = Cl) was more potent than CQ in vitro, and 8 (n = 4; R1 = H) reduced P. berghei parasitemia up to 37% on day 7. The carbonylated PQ derivative 17 (R = Br) was slightly less potent than PQ. The gem-difluoro PQ derivative 20 (R = Cl) exhibited high transmission blockade of the malaria sporogonic cycle in mosquitoes. Compounds 6 and 20 dose-dependently reduced nitric oxide (NO) production and inhibited TNFα production by LPS-stimulated J774A.1 macrophages. Our results indicate a viable and interesting approach in planning new chemical entities that act as transmission-blocking drugs for treating malaria caused by P. falciparum and P. vivax and the anti-inflammatory process related to this disease.
Design and synthesis of new antimalarial agents from 4-aminoquinoline
Solomon, V. Raja,Puri, Sunil K.,Srivastava, Kumkum,Katti
, p. 2157 - 2165 (2005)
This study describes the synthesis of new 4-aminoquinoline derivatives and evaluation of their activity against a chloroquine sensitive strain of P. falciparum in vitro and chloroquine resistant N-67 strain of P. yoelii in vivo. All the analogues were found to form strong complex with hematin and inhibit the β-hematin formation in vitro. These results suggest that these compounds act on heme polymerization target.
4-Aminoquinoline-pyrimidine-aminoalkanols: Synthesis, in vitro antimalarial activity, docking studies and ADME predictions
Tripathi, Mohit,Khan, Shabana I.,Thakur, Anuj,Ponnan, Prija,Rawat, Diwan S.
, p. 3474 - 3483 (2015)
Twenty-four new 4-aminoquinoline-pyrimidine hybrids containing a terminal aliphatic amino-alcohol chain were synthesized and assessed for their antimalarial activity against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum. All of the compounds displayed potent antiplasmodial activities (IC50 values in the range of 0.05-10.47 μM) with no appreciable cytotoxicity towards mammalian cells, up to the highest tested concentration of 12 μM. Molecular docking studies of the most active compounds (8b-8f, 8u and 8v) with both wild type and quadruple mutant Pf-DHFR-TS were performed, which exhibited interactions comparable to conventional folate inhibitors. ADME predictions also revealed favourable pharmacokinetic parameters for the synthesized hybrids, which warrants their suitability for development as potent antimalarials.
β-amino-alcohol tethered 4-aminoquinoline-isatin conjugates: Synthesis and antimalarial evaluation
Nisha,Gut, Jiri,Rosenthal, Philip J.,Kumar, Vipan
, p. 566 - 573 (2014)
A series of β-amino alcohol tethered 4-aminoquinoline-isatin conjugates were synthesized with the aim of probing their antimalarial structure activity relationship. Two of the most active conjugates (11 b and 11 f) exhibited antimalarial efficacy comparable to that of chloroquine, with IC50 values of 11.8 and 13.5 nM, respectively against chloroquine resistant W2 strain of Plasmodium falciparum and are devoid of any cytotoxicity.
Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P. falciparum
Madrid, Peter B.,Liou, Ally P.,DeRisi, Joseph L.,Guy, R. Kiplin
, p. 4535 - 4543 (2006)
Previous data showing that several chloroquine analogues containing an intramolecular hydrogen-bonding motif were potent against multidrug-resistant P. falciparum led to the exploration of the importance of this motif. A series of 116 compounds containing
New amine and urea analogs of ferrochloroquine: Synthesis, antimalarial activity in vitro and electrochemical studies
Chibale,Moss,Blackie,Van Schalkwyk,Smith
, p. 6231 - 6235 (2000)
Amine and urea analogs of ferrochloroquine with varying methylene spacer lengths were synthesised, studied by cyclic voltammetry and evaluated in vitro against a sensitive (D10) and resistant (K1) strain of Plasmodium falciparum. Most analogs were found to be more active than chloroquine in both strains. In D10 ureas were more active than amines and antimalarial activity in this strain correlated well with the length of the methylene spacer and redox potentials. The length of the methylene spacer was a major determinant of antimalarial activity in K1. (C) 2000 Elsevier Science Ltd.
Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth
Gorka, Alexander P.,Alumasa, John N.,Sherlach, Katy S.,Jacobs, Lauren M.,Nickley, Katherine B.,Brower, Jonathan P.,De Dios, Angel C.,Roepe, Paul D.
, p. 356 - 364 (2013)
We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013). Copyright
New pentasubstituted pyrrole hybrid atorvastatin-quinoline derivatives with antiplasmodial activity
Carvalho, Rita C.C.,Martins, Wagner A.,Silva, Tayara P.,Kaiser, Carlos R.,Bastos, Mo?nica M.,Pinheiro, Luiz C.S.,Krettli, Antoniana U.,Boechat, Núbia
, p. 1881 - 1884 (2016)
Cerebral malaria is caused by Plasmodium falciparum. Atorvastatin (AVA) is a pentasubstituted pyrrole, which has been tested as an adjuvant in the treatment of cerebral malaria. Herein, a new class of hybrids of AVA and aminoquinolines (primaquine and chloroquine derivatives) has been synthesized. The quinolinic moiety was connected to the pentasubstituted pyrrole from AVA by a linker group (CH2)n = 2-4 units. The activity of the compounds increased with the size of the carbons chain. Compound with n = 4 and 7-chloroquinolinyl has displayed better activity (IC50 = 0.40 μM) than chloroquine. The primaquine derivative showed IC50 = 1.41 μM, being less toxic and more active than primaquine.
Itaconic acid hybrids as potential anticancer agents
Perkovi?, Ivana,Beus, Maja,Schols, Dominique,Persoons, Leentje,Zorc, Branka
, (2022)
Abstract: In this paper, we report the synthesis of novel hybrids 2–14 based on itaconic acid and fluoroaniline, pyridine, indole and quinoline scaffolds. Itaconic acid is a naturally occurring compound with a Michael acceptor moiety, a key structural feature in several anticancer and antiviral drugs, responsible for the covalent binding of a drug to the cysteine residue of a specific protein. Aromatic parts of the hybrids also come from the substances reported as anticancer or antiviral agents. The synthetic route employed to access the amido-ester hybrids 2–13 used monomethyl itaconate or monomethyl itaconyl chloride and corresponding amines as the starting materials. Dimers 14 and 15 with two aminoindole or mefloquine moieties were prepared from itaconic acid and corresponding amino derivative, using standard coupling conditions (HATU/DIEA). All hybrids exerted anticancer effects in vitro against almost all the tumour cell lines that were evaluated (MCF-7, HCT 116, H460, LN-229, Capan-1, DND-41, HL-60, K-562, Z-138). Solid tumour cells were, in general, more responsive than the haematological cancer cells. The MCF-7 breast adenocarcinoma cell line appeared the most sensitive. Amido-ester 12 with chloroquine core and mefloquine homodimer 15 showed the highest activity with GI50 values between 0.7 and 8.6?μM. In addition, compound 15 also exerted antiviral activity against Zika virus and Coxsackievirus B4 in low micromolar concentrations. Graphic abstract: [Figure not available: see fulltext.].
N-Cinnamoylation of Antimalarial Classics: Effects of Using Acyl Groups Other than Cinnamoyl toward Dual-Stage Antimalarials
Gomes, Ana,Machado, Marta,Lobo, Lis,Nogueira, Fátima,Prudêncio, Miguel,Teixeira, Cátia,Gomes, Paula
, p. 1344 - 1349 (2015)
In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided
Anti-Plasmodium falciparum activity of quinoline-sulfonamide hybrids
Pinheiro, Luiz C.S.,Boechat, Núbia,Ferreira, Maria De Lourdes G.,Júnior, Carlos C.S.,Jesus, Ant?nio M.L.,Leite, Milene M.M.,Souza, Nicolli B.,Krettli, Antoniana U.
, p. 5979 - 5984 (2015)
Fifteen quinoline-sulfonamide hybrids, with a 7-chloroquinoline moiety connected by a linker group to arylsulfonamide moieties with different substituents in the 4-position were synthesized and assayed against Plasmodium falciparum. The compounds displayed high schizonticidal blood activity in vitro, with IC50 values ranging from 0.05 to 1.63 μM, in the anti-HPR2 assay against clone W2-chloroquine-resistant; ten of them showed an IC50 (ranging from 0.05 to 0.40 μM) lower than that of chloroquine and sulfadoxine. Among them, two compounds inhibited Plasmodium berghei parasitemia by 47% and 49% on day 5 after mice inoculation. The most active, in vivo, hybrid 13 is considered to be a new prototype for the development of an antimalarial drug against chloroquine-resistant parasites.
Design and synthesis of quinoline-pyrimidine inspired hybrids as potential plasmodial inhibitors
Kayamba, Francis,Malimabe, Teboho,Ademola, Idowu Kehinde,Pooe, Ofentse Jacob,Kushwaha, Narva Deshwar,Mahlalela, Mavela,van Zyl, Robyn L.,Gordon, Michelle,Mudau, Pertunia T.,Zininga, Tawanda,Shonhai, Addmore,Nyamori, Vincent O.,Karpoormath, Rajshekhar
, (2021/03/22)
Presently, artemisinin-based combination therapy (ACT) is the first-line therapy of Plasmodium falciparum malaria. With the emergence of malaria parasites that are resistant to ACT, alternative antimalarial therapies are urgently needed. In line with this
