- 4,9-Diaminoacridines and 4-Aminoacridines as Dual-Stage Antiplasmodial Hits
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Multi-stage drugs have been prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. Herein, we disclose two novel acridine-based families of compounds that combine the structural features of primaquine and chloroquine. Compounds prepared and studied thus far retained the in vitro activity displayed by the parent drugs against the erythrocytic stages of chloroquine-sensitive and -resistant Plasmodium falciparum strains, and against the hepatic stages of Plasmodium berghei, hence acting as dual-stage antiplasmodial hits.
- Fonte, Mélanie,Tassi, Natália,Fontinha, Diana,Bouzón-Arnáiz, Inés,Ferraz, Ricardo,Araújo, Maria J.,Fernàndez-Busquets, Xavier,Prudêncio, Miguel,Gomes, Paula,Teixeira, Cátia
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Read Online
- Preparation method of primaquine phosphate
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The invention discloses a preparation method of primaquine phosphate, which is characterized by comprising the following steps of: adding a secondary condensate, ethanol and hydrazine hydrate into a reaction container, introducing nitrogen for protection, stirring in a dark place, heating to 78-80 DEG C, carrying out reflux reaction until the reaction is complete, evaporating ethanol under normal pressure until the internal temperature is increased to 92-95 DEG C, adding water, stirring, heating to 58-62 DEG C to enable no solid to suspend, cooling to 40-50 DEG C, dropwise adding a sodium hydroxide solution with the mass concentration of 25-30% while stirring to enable the pH to be 13-14, stirring, adding methylbenzene, stirring, standing for layering, adding water into an organic phase for washing, then decolorizing with activated carbon, filtering and concentrating to obtain free primaquine oil, and adding dichloroethane for crystallization to obtain free primaquine. By adjusting process parameters (such as reaction temperature, time, light shielding, nitrogen protection and charging sequence) of each step, a dichloroethane crystallization process of free primaquine is added, the purity of a finished product is greater than 99.5%, the content of a single impurity is less than 0.2%, and the yield is high.
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Paragraph 0026-0038
(2021/08/14)
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- Regiodivergent Conversion of Alkenes to Branched or Linear Alkylpyridines
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Herein we report a practical protocol for the visible-light-induced regiodivergent radical hydropyridylation of unactivated alkenes using pyridinium salts. This approach provides a unified synthetic platform to control the regioselectivity of the synthesis of linear or branched C4-alkylated pyridines. A remarkable selectivity switch from the anti-Markovnikov to the Markovnikov product can be achieved by the addition of tetrabutylammonium bromide. The versatility of this protocol is further demonstrated based on the late-stage functionalization in pharmaceuticals.
- Hong, Sungwoo,Jung, Sungwoo,Kim, Minseok,Koo, Yejin,Shin, Sanghoon
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supporting information
(2022/01/20)
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- Antimalarial activity of primaquine operates via a two-step biochemical relay
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Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H2O2, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.
- Camarda, Grazia,Jirawatcharadech, Piyaporn,Priestley, Richard S.,Saif, Ahmed,March, Sandra,Wong, Michael H. L.,Leung, Suet,Miller, Alex B.,Baker, David A.,Alano, Pietro,Paine, Mark J. I.,Bhatia, Sangeeta N.,O’Neill, Paul M.,Ward, Stephen A.,Biagini, Giancarlo A.
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- Endoperoxide-8-aminoquinoline hybrids as dual-stage antimalarial agents with enhanced metabolic stability
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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. The hybrid compounds inhibited development of intra-erythrocytic forms of the multidrug-resistant Plasmodium falciparum W2 strain, with EC50 values in the nM range, and with low cytotoxicity against mammalian cells. The compounds also inhibited the development of P. berghei liver stage parasites, with the most potent compounds displaying EC50 values in the low μM range. SAR analysis revealed that unbranched linkers between the endoperoxide and 8-aminoquinoline pharmacophores are most beneficial for dual antiplasmodial activity. Importantly, hybrids were significantly more potent than a 1:1 mixture of 8-aminoquinoline-tetraoxane, highlighting the superiority of the hybrid approach over the combination therapy. Furthermore, aryl substituents at C-5 of the 8-aminoquinoline moiety improve the compounds' metabolic stability when compared with their primaquine (i.e. C-5 unsubstituted) counterparts. Overall, this study reveals that blocking the quinoline C-5 position does not result in loss of dual-stage antimalarial activity, and that tetraoxane-8- aminoquinoline hybrids are an attractive approach to achieve elimination of exo- and intraerythrocytic parasites, thus with the potential to be used in malaria eradication campaigns.
- Capela, Rita,Magalh?es, Joana,Miranda, Daniela,Machado, Marta,Sanches-Vaz, Margarida,Albuquerque, Inês S.,Sharma, Moni,Gut, Jiri,Rosenthal, Philip J.,Frade, Raquel,Perry, Maria J.,Moreira, Rui,Prudêncio, Miguel,Lopes, Francisca
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- Site-Selective Aliphatic C-H Chlorination Using N-Chloroamides Enables a Synthesis of Chlorolissoclimide
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Methods for the practical, intermolecular functionalization of aliphatic C-H bonds remain a paramount goal of organic synthesis. Free radical alkane chlorination is an important industrial process for the production of small molecule chloroalkanes from simple hydrocarbons, yet applications to fine chemical synthesis are rare. Herein, we report a site-selective chlorination of aliphatic C-H bonds using readily available N-chloroamides and apply this transformation to a synthesis of chlorolissoclimide, a potently cytotoxic labdane diterpenoid. These reactions deliver alkyl chlorides in useful chemical yields with substrate as the limiting reagent. Notably, this approach tolerates substrate unsaturation that normally poses major challenges in chemoselective, aliphatic C-H functionalization. The sterically and electronically dictated site selectivities of the C-H chlorination are among the most selective alkane functionalizations known, providing a unique tool for chemical synthesis. The short synthesis of chlorolissoclimide features a high yielding, gram-scale radical C-H chlorination of sclareolide and a three-step/two-pot process for the introduction of the β-hydroxysuccinimide that is salient to all the lissoclimides and haterumaimides. Preliminary assays indicate that chlorolissoclimide and analogues are moderately active against aggressive melanoma and prostate cancer cell lines.
- Quinn, Ryan K.,K?nst, Zef A.,Michalak, Sharon E.,Schmidt, Yvonne,Szklarski, Anne R.,Flores, Alex R.,Nam, Sangkil,Horne, David A.,Vanderwal, Christopher D.,Alexanian, Erik J.
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supporting information
p. 696 - 702
(2016/02/03)
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- Synthesis method of antimalarial drug primaquine phosphate intermediate N-(4-bromopentyl)phthalimide
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The invention provides a synthesis method of an antimalarial drug primaquine phosphate intermediate N-(4-bromopentyl)phthalimide. N-(4-bromopentyl)phthalimide is an important intermediate of an antimalarial drug primaquine phosphate. The method comprises the following steps: carrying out a condensation reaction on 5-chloro-1-pentene and phthalimide potassium salt, and carrying out an addition reaction on a condensation product 5-(o-phthalimido)-1-pentene and hydrogen bromide to obtain the final product. The method has the advantages of low cost of raw materials, high conversion rate, high purity of the final product, mild conditions of every reaction, and simple and easily controlled reaction process.
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Paragraph 0059; 0060; 0061
(2017/01/02)
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- Site-selective aliphatic C-H bromination using N -bromoamides and visible light
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Transformations that selectively functionalize aliphatic C-H bonds hold significant promise to streamline complex molecule synthesis. Despite the potential for site-selective C-H functionalization, few intermolecular processes of preparative value exist. Herein, we report an approach to unactivated, aliphatic C-H bromination using readily available N-bromoamide reagents and visible light. These halogenations proceed in useful chemical yields, with substrate as the limiting reagent. The site selectivities of these radical-mediated C-H functionalizations are comparable (or superior) to the most selective intermolecular C-H functionalizations known. With the broad utility of alkyl bromides as synthetic intermediates, this convenient approach will find general use in chemical synthesis.
- Schmidt, Valerie A.,Quinn, Ryan K.,Brusoe, Andrew T.,Alexanian, Erik J.
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supporting information
p. 14389 - 14392
(2014/12/10)
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- AMINOQUINOLINIUM SALTS, METHODS OF THEIR PRODUCTION AND THEIR USE AS ACTIVE AGENTS FOR BIOTECHNOLOGICAL AND MEDICAL APPLICATIONS AGAINST BINARY TOXINS
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The present invention relates to aminoquinoline salts, their uses and to methods of synthesizing such aminoquinoline salts. Moreover, the present invention relates to compositions comprising aminoquinoline salts in accordance with the present invention. The present invention relates to bioactive compounds from the class of aminoquinoline compounds, and in particular their inhibitory effects on the binary toxins of an AB-type of a number of bacteria, such as Clostridium perfringens, Clostridium botulinum, and Bacillus anthracis. The invention also relates to the use of these aminoquinoline compounds as drugs, more particularly as drugs for the treatment of bacterial infections, even more particularly bacterial infections caused by bacteria which produce pore forming toxins of a binary type. The present invention also relates to methods of producing the compounds in accordance with the present invention.
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Page/Page column 31
(2012/04/17)
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- MODULATORS OF ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTORS AND THERAPEUTIC USES THEREOF
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Compounds with α7 nicotinic acetylcholine receptor (α7 nAChR) agonistic activity, processes for their preparation, pharmaceutical compositions containing the same and the use thereof for the treatment of neurological and psychiatric diseases.
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Page/Page column 41
(2010/11/28)
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- Process for the preparation of anti-malarial drugs
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The invention relates to novel intermediates and processes for the preparation of quinoline compounds useful as anti-malarial drugs and novel intermediates useful in the process. A process for the preparation of a compound of formula (I) in which R1is C1-6alkyl; R2and R3are independently hydrogen, halogen, trifluoromethyl or C1-6alkoxy; R4is C1-6alkyl; R5is hydrogen or C1-6alkyl; and R6or amino which comprises reacting a compound of formula (II) in which R1, R4and R5are as defined in formula (I) and X is a leading group with a compound of formula (III).
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