- Repurposing primaquine as a polyamine conjugate to become an antibiotic adjuvant
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In our search for new antibiotic adjuvants as a novel strategy to deal with the emergence of multi-drug resistant (MDR) bacteria, a series of succinylprimaquine-polyamine (SPQ-PA) conjugates and derivatives of a cationic amphiphilic nature have been prepared. Evaluation of these primaquine conjugates for intrinsic antimicrobial properties and the ability to restore the antibiotic activity of doxycycline identified two derivatives, SPQ-PA3-8-3 and SPQ-PA3-10-3 that exhibited intrinsic activity against the Gram-positive bacteria Staphylococcus aureus and the yeast Cryptococcus neoformans. None of the analogues were active against the Gram-negative bacterium Pseudomonas aeruginosa. However, in the presence of a sub-therapeutic amount of doxycycline (4.5 μM), both SPQ-PA3-4-3 and SPQ-PA3-10-3 compounds displayed potent antibiotic adjuvant properties against P. aeruginosa, with MIC's of 6.25 μM. A series of derivatives were prepared to investigate the structure-activity relationship that explored the influence of both a simplified aryl lipophilic substituent and variation of the length of the polyamine scaffold on observed intrinsic antimicrobial properties and the ability to potentiate the action of doxycycline against P. aeruginosa.
- Bourguet-Kondracki, Marie-Lise,Brunel, Jean Michel,Cadelis, Melissa M.,Chen, Dan,Copp, Brent R.,Edmeades, Liam R.,Pearce, A. Norrie,Troudi, Azza
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- Itaconic acid hybrids as potential anticancer agents
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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.].
- Beus, Maja,Perkovi?, Ivana,Persoons, Leentje,Schols, Dominique,Zorc, Branka
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- Synthesis of primaquine glyco-conjugates as potential tissue schizontocidal antimalarial agents
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Primaquine (PQ) is the only drug used to prevent relapse of malaria due to P. vivax and P. ovale, by eradicating the dormant liver form of the parasite (hypnozoites). The side-effects associated with PQ limits is uses in treatment of malaria. To overcome the premature oxidative deamination and to increase the life span of drug in the biological system, the novel glyco-conjugates of PQ were synthesized by coupling of primaquine with hexoses in phosphate buffer. The saccharide part of the hybrid molecules thought to direct the drug to the liver, where hypnozoites resides. All the synthesized compounds were fully characterized and evaluated for their radical curative activities. The three compounds viz glucoside (15a), galactoside (15b) and mannoside (15c) with high activity were tested for their activity in rhesus monkeys where the most active compound 15b showed twofold activity (100% radical curative activity at 1.92?mmol/kg) than the standard drug PQ diphosphate (3.861?mmol/kg). It is proposed that results from these studies may be advantageous to develop a new potent tissue schizonticide antimalarial compound.
- Azad, Chandra S.,Saxena, Mridula,Siddiqui, Arif J.,Bhardwaj, Jyoti,Puri, Sunil K.,Dutta, Guru P.,Anand, Nitya,Saxena, Anil K.
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p. 254 - 261
(2017/07/13)
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- New pentasubstituted pyrrole hybrid atorvastatin-quinoline derivatives with antiplasmodial activity
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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.
- 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
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supporting information
p. 1881 - 1884
(2016/04/05)
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- Targeting the erythrocytic and liver stages of malaria parasites with s-triazine-based hybrids
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A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic-stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells. The most effective blood-schizontocidal s-triazine derivatives were then screened for activity against the liver stage of malaria parasites. The s-triazine hybrid containing two 8-aminoquinoline moieties and one chlorine atom emerged as the most potent against P. berghei liver-stage infection, active in the low nanomolar region, combined with good metabolic stability in rat liver microsomes. These results indicate that s-triazine-8-aminoquinoline-based hybrids are excellent starting points for lead optimization as dual-stage antimalarials.
- Rodrigues, Catarina A. B.,Frade, Raquel F. M.,Albuquerque, Inês S.,Perry, Maria J.,Gut, Jiri,Machado, Marta,Rosenthal, Philip J.,Prudêncio, Miguel,Afonso, Carlos A. M.,Moreira, Rui
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supporting information
p. 883 - 890
(2015/05/05)
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- COMPOSITION AND METHODS FOR SITE-SPECIFIC DRUG DELIVERY TO TREAT MALARIA AND OTHER LIVER DISEASES
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A system for selectively delivering drugs to target tissues is provided. The system includes a drug-linker-saccharide-drug conjugate (D-L-A-D1). The linker includes a functional group that is recognized and cleaved by enzyme in the target phases. The recognition segment is preferably a malaria drugs. The carrier is preferably hydrophilic, biodegradable and biocompatible particle. Any drug may be delivered using a conjugate prepared according to the invention.
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Page/Page column
(2014/04/18)
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- A carbamate-based approach to primaquine prodrugs: Antimalarial activity, chemical stability and enzymatic activation
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O-Alkyl and O-aryl carbamate derivatives of the antimalarial drug primaquine were synthesised as potential prodrugs that prevent oxidative deamination to the inactive metabolite carboxyprimaquine. Both O-alkyl and O-aryl carbamates undergo hydrolysis in alkaline and pH 7.4 phosphate buffers to the parent drug, with O-aryl carbamates being ca. 106-10 10 more reactive than their O-alkyl counterparts. In human plasma O-alkyl carbamates were stable, whereas in contrast their O-aryl counterparts rapidly released the corresponding phenol product, with primaquine being released only slowly over longer incubation periods. Activation of the O-aryl carbamates in human plasma appears to be catalysed by butyrylcholinesterase (BuChE), which leads to carbamoylation of the catalytic serine of the enzyme followed by subsequent slow enzyme reactivation and release of parent drug. Most of the O-aryl and O-alkyl carbamates are activated in rat liver homogenates with half-lives ranging from 9 to 15 h, while the 4-nitrophenyl carbamate was hydrolysed too rapidly to determine an accurate rate constant. Antimalarial activity was studied using a model consisting of Plasmodium berghei, Balb C mice and Anopheles stephensi mosquitoes. When compared to controls, ethyl and n-hexyl carbamates were able to significantly reduce the percentage of infected mosquitos as well as the mean number of oocysts per infected mosquito, thus indicating that O-alkyl carbamates of primaquine have the potential to be developed as transmission-blocking antimalarial agents.
- Mata, Graa,Do Rosário, Virgílio E.,Iley, Jim,Constantino, Luís,Moreira, Rui
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experimental part
p. 886 - 892
(2012/03/22)
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- Synthesis, cytotoxicity and antimalarial activity of ferrocenyl amides of 4-aminoquinolines
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Series of 4-aminoquinolines bearing an amino side chain linked to the ferrocene moiety through an amide bond were synthesized and evaluated for their antimalarial activity against both chloroquine-sensitive (D10, CQ-S) and chloroquine-resistant (Dd2, CQ-R) strains of Plasmodium falciparum. They were also tested for cytotoxicity against Chinese Hamster Ovarian (CHO) cells. Amide 12 featuring propyl side chain linked to the ferrocene ring was the most active of all tested compounds. With an IC50 value of 0.08 μg/mL, this amide showed 1.5-fold higher activity than chloroquine diphosphate (IC 50 = 0.12 μg/mL) against the resistant strain, with a selectivity index of 550 indicating its high selectivity towards the parasite. Derivatives which were equipotent against both strains also showed up to ten-fold increase in activity compared to primaquine. ECV · Editio Cantor Verlag.
- N'Da, David D.,Breytenbach, Jaco C.,Smith, Peter J.,Lategan, Carmen
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experimental part
p. 627 - 635
(2011/05/19)
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- Anti-tumoral activity of imidazoquines, a new class of antimalarials derived from primaquine
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The growth inhibitory activity of imidazoquines, antimalarial imidazolidin-4-ones derived from primaquine, on human cancer cell lines HT-29, Caco-2, and MCF-7 has been evaluated. Primaquine, N-dipeptidyl-primaquine derivatives, and other quinolines have b
- Fernandes, Iva,Vale, Nuno,de Freitas, Victor,Moreira, Rui,Mateus, Nuno,Gomes, Paula
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supporting information; experimental part
p. 6914 - 6917
(2010/08/06)
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- NEW OLIGOMERIC CONJUGATES LIABLE TO TRANSFER BIOLOGICAL MOLECULES INTO CELLS
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The invention relates to a positively charged oligomeric conjugate, containing an oligomer with a polymerization degree (PD) from 5 to 50, preferably 10 to 40 and more preferably 20, formed from monomeric components having free NH3 in a number equal to or higher than 50 % of the polymerization degree. In particular, the invention provides new oligomeric conjugates of histidylated oligolysine liable to allow the transfer of oligonucleotides, peptides and oligosides into cells.
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- Biodegradable microspheres. 17. Lysosomal degradation of primaquine- peptide spacer arms
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The pharmacological activity of drugs bound to lysosomotropic drug carriers will depend on the rate of release of the drugs from the drug- carrier complex. We have now studied the enzymatic release of primaquine (PQ) from two groups of peptide-PQ derivatives by their incubation with rat liver lysosomal fraction. The derivatives have the general structure NH2-X-Leu- Ala-Y-PQ and are intended to be coupled via their free α-amino group to starch microparticles. In the first group, Y was varied, being Leu, Tyr, Lys, or Asp, while X was Ala. In the second one, X was varied, being Ala, Tyr, Lys, or Asp, while Y was Leu. Thus, a systematic study of the significance of the varying amino acid composition of the tetrapeptides, which can serve as spacer arms in the microparticle-drug complexes, for the lysosomal release of PQ was possible. In addition, some ε-aminocaproic acid-PQ derivatives, which lack a free α-amino group, were incubated. This was done to study the importance of enzymes, other than aminopeptidases, during lysosomal degradation of these derivatives. The pattern and rate of degradation of all PQ derivatives was followed by HPLC analysis. The results obtained show that endopeptidases, as well as mono- and diaminopeptidases, degrade the derivatives. PQ cannot be cleaved directly from the derivatives by any carboxypeptidase-like enzyme. Asp peptides are digested slowly in the lysosomal fraction. The temporal aspects of reactions were quantitated using a kinetic model, in which first-order rate constants of all the steps of each peptide degradation sequence were estimated simultaneously.
- Borissova,Stjarnkvist,Karlsson,Sjoholm
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p. 256 - 262
(2007/10/02)
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- Treatment of amyloidosis associated with Alzheimer disease
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Agents which modulate or affect the intracellular trafficking and processing of proteins in the mammalian cell can be utilized to affect the trafficking and processing of APP, thereby inhibiting production of Alzheimer type amyloidosis. Particularly useful agents are chloroquine and its related derivatives such as primaquine.
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- New compounds which are active against the tissue forms of malaria and method of preparation
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The invention relates to new quinoline derivatives containing a free amine group and having antimalarial properties, in particular new primaquine derivatives or their addition salts with acids, and to a method for preparing them. According to the invention, these new derivatives are represented schematically by the formula: in which PQ denotes quinolines containing a free amine group and having antimalarial properties, in particular primaquine; X denotes an amino acid or a peptide of 2 to 4 amino acids; and the PQ-X bond being a covalent peptide bond between the free amine group of PQ and the carboxyl group of X, the PQ-X covalent bond being stable in serum and resistant to lysosomal hydrolases. In an embodiment of the invention, the amino acid or the first amino acid of a peptide linked to PQ is gamma-L-glutamic acid or beta-aspartic acid linked to PQ via their beta- or gamma-carboxyl group, or L-pyroglutamic acid or aspartic acid linked to PQ via their alpha-carboxyl group.
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