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4-Aminoquinoline Compound

Elizabeth A Hall, Jon E Ramsey, Zhihua Peng, Davit Hayrapetyan, Viacheslav Shkepu, Bruce O'Rourke, William Geiger, Kevin Lam, Claire F Verschraegen
Autophagy has emerged as a mechanism critical to both tumorigenesis and development of resistance to multiple lines of anti-cancer therapy. Therefore, targeting autophagy and alternative cell death pathways has arisen as a viable strategy for refractory tumors. The anti-malarial 4-aminoquinoline compounds chloroquine and hydroxychloroquine are currently being considered for re-purposing as anti-cancer therapies intended to sensitize different tumors by targeting the lysosomal cell death pathway. Here, we describe a novel organometallic chloroquine derivative, cymanquine, that exhibits enhanced bioactivity compared to chloroquine in both normal, and reduced pH tumor microenvironments, thus overcoming a defined limitation of traditional 4-aminoquinolines...
March 25, 2018: Journal of Cellular Biochemistry
Rita Capela, Joana Magalhães, Daniela Miranda, Marta Machado, Margarida Sanches-Vaz, Inês S Albuquerque, Moni Sharma, Jiri Gut, Philip J Rosenthal, Raquel Frade, Maria J Perry, Rui Moreira, Miguel Prudêncio, Francisca Lopes
Hybrid compounds may play a critical role in the context of the malaria eradication agenda, which will benefit from therapeutic tools active against the symptomatic erythrocytic stage of Plasmodium infection, and also capable of eliminating liver stage parasites. To address the need for efficient multistage antiplasmodial compounds, a small library of 1,2,4,5-tetraoxane-8- aminoquinoline hybrids, with the metabolically labile C-5 position of the 8-aminoquinoline moiety blocked with aryl groups, was synthesized and screened for antiplasmodial activity and metabolic stability...
April 10, 2018: European Journal of Medicinal Chemistry
Jelena Konstantinović, Erkan Kiris, Krishna P Kota, Johanny Kugelman-Tonos, Milica Videnović, Lisa H Cazares, Nataša Terzić Jovanović, Tatjana Ž Verbić, Boban Andjelković, Allen J Duplantier, Sina Bavari, Bogdan A Šolaja
The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min postintoxication...
February 22, 2018: Journal of Medicinal Chemistry
Nicoletta Basilico, Silvia Parapini, Anna Sparatore, Sergio Romeo, Paola Misiano, Livia Vivas, Vanessa Yardley, Simon L Croft, Annette Habluetzel, Leonardo Lucantoni, Laurent Renia, Bruce Russell, Rossarin Suwanarusk, Francois Nosten, Giulio Dondio, Chiara Bigogno, Daniela Jabes, Donatella Taramelli
Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine ( Lupinus luteus ). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication...
December 1, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Mukesh C Joshi, John Okombo, Samkele Nsumiwa, Jeffrey Ndove, Dale Taylor, Lubbe Wiesner, Roger Hunter, Kelly Chibale, Timothy J Egan
Emergence of drug resistant Plasmodium falciparum including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and in which the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve druglikeness...
December 28, 2017: Journal of Medicinal Chemistry
Anu Rani, Amandeep Singh, Jiri Gut, Philip J Rosenthal, Vipan Kumar
Microwave promoted high yielding synthesis of 4-aminoquinoline-phthalimides was developed with an aim to evaluate their anti-plasmodial potential. The scaffolds with longer spacer length (n = 6, 8) between two pharmacophores and a halogen substituent on the phthalimide ring displayed good antiplasmodial activity. Compound 5w, with an optimum combination of hexyl chain as spacer along with a tetra-bromophthalimide ring proved to be most potent and non-cytotoxic among the series exhibiting an IC50 value of 0...
January 1, 2018: European Journal of Medicinal Chemistry
Edgar A Valverde, Angel H Romero, María E Acosta, Neira Gamboa, Genesis Henriques, Juan R Rodrigues, Carlos Ciangherotti, Simón E López
Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert-butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I and II clinical trials, respectively. Nevertheless, pharmacodynamic studies have demonstrated that isoquine is highly sensitive to form O-glucuronide metabolite, which may affect its accumulation in tissues. To avoid the O-glucuronide formation and its negative influence in the accumulation process, a series of novel five dehydroxy isoquine derivatives were designed and prepared herein as potential antimalarial agents...
March 25, 2018: European Journal of Medicinal Chemistry
Benedikt Ley, Germana Bancone, Lorenz von Seidlein, Kamala Thriemer, Jack S Richards, Gonzalo J Domingo, Ric N Price
Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at risk of severe haemolysis following the administration of 8-aminoquinoline compounds. Primaquine is the only widely available 8-aminoquinoline for the radical cure of Plasmodium vivax. Tafenoquine is under development with the potential to simplify treatment regimens, but point-of-care (PoC) tests will be needed to provide quantitative measurement of G6PD activity prior to its administration. There is currently a lack of appropriate G6PD PoC tests, but a number of new tests are in development and are likely to enter the market in the coming years...
September 11, 2017: Malaria Journal
Reza Ranjbar-Karimi, Alireza Poorfreidoni
A series of hybrid of 4-aminoquinoline and fluorinated pyridine derivatives were synthesized and their chemical structure were confirmed by19 F-NMR,1 H-NMR,13 C-NMR and FT-IR. All compounds were tested against one Gram-positive and one Gram-negative bacteria to assess their in vitro antibacterial activity. Compounds 10A: , 10B: , 11A: and 12B: showed moderate antibacterial activity against Gram-positive bacterium, Staphylococcus aureus.
January 2018: Drug Research
Sukriti Singh, Surya K, Raghavan B Sunoj
Transition-metal-catalyzed C(sp(3))-H bond activation in aliphatic compounds are of current interest. Lack of mechanistic insights on Ni-catalyzed C(sp(3))-H activation using 8-aminoquinoline as a directing group motivated us to examine an interesting direct arylation of an aliphatic tertiary amide by using density functional theory. The catalysis employed Ni(II) precatalyst, 4-iodoanisole as an arylating agent, sodium carbonate, and mesitylenic acid as additives in DMF solvent. Examination of a comprehensive set of mechanistic pathways helped us learn that the most preferred route begins with a bidentate chelate binding of deprotonated substrate to the Ni...
August 25, 2017: Journal of Organic Chemistry
Sharné-Maré Fitzroy, Johandie Gildenhuys, Tania Olivier, Ndivhuwo Olga Tshililo, David Kuter, Katherine Allison de Villiers
The throughput of a biomimetic lipid-mediated assay used to investigate the effects of inhibitors on the kinetics of β-hematin formation has been optimized through the use of 24-well microplates. The rate constant for β-hematin formation mediated by monopalmitoyl-rac-glycerol was reduced from 0.17 ± 0.04 min-1 previously measured in Falcon tubes to 0.019 ± 0.002 min-1 in the optimized assay. While this necessitated longer incubation times, transferring aliquots from multiple 24-well plates to a single 96-well plate for final absorbance measurements actually improved the overall turnaround time per inhibitor...
August 1, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
Erin L Dodd, Dagobert Tazoo, D Scott Bohle
Solution NMR has been used in tandem with a diamagnetic non-iron heme model compound as a simple and effective tool to rapidly probe the structures of the bound complexes formed between the metalloporphyrin and antimalarial drugs from the 4-aminoquinoline, 4-methylenehydroxylquinoline, and 8-aminoquinoline subfamilies. The ability of gallium(III) protoporphyrin IX to mimic heme chemistry is exploited. The 4-aminoquinolines quinacrine and amodiaquine and two novel 3-halo chloroquine analogues are found to bind to the metalloporphyrin through hydrogen-bonding and stacking interactions, while halofantrine and the 4-methylenehydroxylquinolines, quinine and mefloquine bind through the alcohol group of the drug...
July 17, 2017: Inorganic Chemistry
Marcelle L F Bispo, Camilo H S Lima, Laura N F Cardoso, André L P Candéa, Flávio A F M Bezerra, Maria C S Lourenço, Maria G M O Henriques, Ricardo B Alencastro, Carlos R Kaiser, Marcus V N Souza, Magaly G Albuquerque
In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis...
June 9, 2017: Pharmaceuticals
Arezoo Rafiee Parhizgar, Azar Tahghighi
Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities...
March 2017: Iranian Journal of Medical Sciences
Ivana Aleksić, Sandra Šegan, Filip Andrić, Mario Zlatović, Ivana Moric, Dejan M Opsenica, Lidija Senerovic
Antibiotic resistance has become a serious global threat to public health; therefore, improved strategies and structurally novel antimicrobials are urgently needed to combat infectious diseases. Here we report a new type of highly potent 4-aminoquinoline derivatives as quorum sensing inhibitors in Serratia marcescens and Pseudomonas aeruginosa, exhibiting weak bactericidal activities (minimum inhibitory concentration (MIC) > 400 μM). Through detailed structure-activity study, we have identified 7-Cl and 7-CF3 substituted N-dodecylamino-4-aminoquinolines (5 and 10) as biofilm formation inhibitors with 50% biofilm inhibition at 69 μM and 63 μM in S...
May 19, 2017: ACS Chemical Biology
Rohit Kholiya, Shabana I Khan, Aparna Bahuguna, Mohit Tripathi, Diwan S Rawat
A series of 4-aminoquinoline-piperonyl-pyrimidine hybrids were synthesized with the aim of identifying compounds with enhanced antimalarial activity. All the synthesized molecules were evaluated in vitro against cultured Plasmodium falciparum W2 and D6 strains and exhibited potent antiplasmodial activities with IC50 values in the range of 0.02-5.16 μM. Out of the 22 synthesised hybrids, 12 were found to be better (up to eight-fold more active) than chloroquine (CQ), particularly against the CQ-resistant W2 strain of P...
May 5, 2017: European Journal of Medicinal Chemistry
Preeti S Salve, Shankar G Alegaon, Dharmarajan Sriram
An efficient three-component, one-pot protocol is described for the synthesis of biologically interesting 2-(benzylideneamino)-N-(7-chloroquinolin-4-yl)benzohydrazide derivatives from isatoic anhydride, 7-chloro-4-hydrazinylquinoline and aromatic and/or hetero aromatic aldehydes under catalyst free condensation by using water as reaction media. All synthesized compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis (MTB) and cytotoxicity activity against normal VERO cell lines...
April 15, 2017: Bioorganic & Medicinal Chemistry Letters
Alistair J Fielding, Valentina Lukinović, Philip G Evans, Said Alizadeh-Shekalgourabi, Roger H Bisby, Michael G B Drew, Verity Male, Alessio Del Casino, James F Dunn, Laura E Randle, Nicola M Dempster, Lutfun Nahar, Satyajit D Sarker, Fabián G Cantú Reinhard, Sam P de Visser, Mike J Dascombe, Fyaz M D Ismail
Antimalarials can interact with heme covalently, by π⋅⋅⋅π interactions or by hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated by using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen because of electronic rather than steric factors. In gas-phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen...
May 17, 2017: Chemistry: a European Journal
Shiv Shyam Maurya, Shabana I Khan, Aparna Bahuguna, Deepak Kumar, Diwan S Rawat
A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots...
March 31, 2017: European Journal of Medicinal Chemistry
Saulo Fehelberg Pinto Braga, Luan Carvalho Martins, Elany Barbosa da Silva, Policarpo Ademar Sales Júnior, Silvane Maria Fonseca Murta, Alvaro José Romanha, Wai Tuck Soh, Hans Brandstetter, Rafaela Salgado Ferreira, Renata Barbosa de Oliveira
Analogues of 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]indol-4-amine 1, a known cruzain inhibitor, were synthesized using a molecular simplification strategy. Five series of analogues were obtained: indole, pyrimidine, quinoline, aniline and pyrrole derivatives. The activity of the compounds was evaluated against the enzymes cruzain and rhodesain as well as against Trypanosoma cruzi amastigote and trypomastigote forms. The 4-aminoquinoline derivatives showed promising activity against both enzymes, with IC50 values ranging from 15 to 125µM...
March 15, 2017: Bioorganic & Medicinal Chemistry
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