11 research outputs found
Novi derivati 9-aminoakridina kao inhibitori botulinum neurotoksina i P. falciparum parazita malarije
Steroidal and adamantane aminoacridine derivatives were prepared and tested as both botulinum neurotoxin (BoNT) inhibitors and antimalarials.. Steroid-bound acridines provided good potency against both the BoNT/A and BoNT/B light chains (LCs). The observed inhibition of the BoNT/B LC by ca. 50 % is the highest attained inhibitory activity against this serotype by acridine-based compounds to date. With respect to the antimalarial activity, the adamantane acridines were the most potent derivatives (IC50 = 6-9 nM, SI gt 326), indicating that an adamantyl group is a better carrier than a steroidal motif for this indication.Sintetisani su derivati steroidnih i adamantil-akridina i ispitana je njihova inhibitorna aktivnost prema botulinum neurotoksinima (BoNT) i parazitu malarije. Steroidni akridini pokazuju dobru inhibiciju prema kratkom nizu (LCs) BoNT/A i BoNT/B. Ostvarena inhibicija BoNT/B LC od oko 50% je najviÅ”a postignuta vrednost akridinskih derivata prema ovom serotipu. Adamantil-akridinski derivati su pokazali najveÄu antimalarijsku aktivnost (IC50 u opsegu 6-9 nM, SI gt 326), pokazujuÄi da je adamantil-grupa bolji nosaÄ farmakofore u poreÄenju sa steroidnim, prema ovoj indikaciji.
Novi derivati 4-aminohinolina kao umereni inhibitori parazita
Synthesis of novel aminoquinoline derivatives has been accomplished and their activity against malaria strains has been examined. The compounds showed moderate in vitro antimalarial activity against two P. falciparum strains, 3D7 (CQ susceptible clone) and Dd2 (CQ resistant clone). Three aminoquinolines were further examined for antimalarial efficacy in a mouse model using a modified Thompson test. In this model, mice were infected with P. berghei-infected red blood cells, and drugs were administered orally. Antimalarial 3 was found toxic at a dose of 320 (mg/kg)/day in 3/6 mice, however, 2/6 mice of the same group survived through day 31, and one of them was cured
Supplementary data for article: Opsenica, I.; Tot, M.; Gomba, L.; Nuss, J. E.; Sciotti, R. J.; Bavari, S.; Burnett, J. C.; Å olaja, B. A. 4-Amino-7-Chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity. Journal of Medicinal Chemistry 2013, 56 (14), 5860ā5871. https://doi.org/10.1021/jm4006077
Supporting information for: [https://doi.org/10.1021/jm4006077]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1381
Supplementary data for article: Opsenica, I.; Tot, M.; Gomba, L.; Nuss, J. E.; Sciotti, R. J.; Bavari, S.; Burnett, J. C.; Å olaja, B. A. 4-Amino-7-Chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity. Journal of Medicinal Chemistry 2013, 56 (14), 5860ā5871. https://doi.org/10.1021/jm4006077
Supporting information for: [https://doi.org/10.1021/jm4006077]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1381
Supplementary data for article: Opsenica, I. M.; VerbiÄ, T. Ž.; Tot, M.; Sciotti, R. J.; Pybus, B. S.; DjurkoviÄ-DjakoviÄ, O.; SlaviÄ, K.; Å olaja, B. A. Investigation into Novel Thiophene- and Furan-Based 4-Amino-7-Chloroquinolines Afforded Antimalarials That Cure Mice. Bioorganic and Medicinal Chemistry 2015, 23 (9), 2176ā2186. https://doi.org/10.1016/j.bmc.2015.02.061
Supplementary material for: [https://doi.org/10.1016/j.bmc.2015.02.061]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1691
Supplementary data for the article: TerziÄ, N.; KonstantinoviÄ, J.; Tot, M.; BurojeviÄ, J.; DjurkoviÄ-DjakoviÄ, O.; SrbljanoviÄ, J.; Å tajner, T.; VerbiÄ, T.; ZlatoviÄ, M.; Machado, M.; et al. Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials? Journal of Medicinal Chemistry 2016, 59 (1), 264ā281. https://doi.org/10.1021/acs.jmedchem.5b01374
Supplementary material for: [https://doi.org/10.1021/acs.jmedchem.5b01374]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2036
New 9-aminoacridine derivatives as inhibitors of Botulinum neurotoxins and P. falciparum malaria
Steroidal and adamantane aminoacridine derivatives were prepared and tested
as both botulinum neurotoxin (BoNT) inhibitors and antimalarials.
Steroid-bound acridines provided good potency against both the BoNT/A and
BoNT/B light chains (LCs). The observed inhibition of the BoNT/B LC by ca.
50% is the highest attained inhibitory activity against this serotype by
acridine-based compounds to date. With respect to antimalarial activity,
adamantane acridines were the most potent derivatives (IC50 = 6-9 nM, SI >
326), indicating that an adamantyl group is a better carries than a steroidal
motif for this indication. [Projekat Ministarstva nauke Republike Srbije, br.
172008
Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice
We herein report the design and synthesis of a novel series of thiophene-and furan-based aminoquinoline derivatives which were found to be potent antimalarials and inhibitors of b-hematin polymerization. Tested compounds were 3-71 times more potent in vitro than CQ against chloroquine-resistant (CQR) W2 strain with benzonitrile 30 being as active as mefloquine (MFQ), and almost all synthesized aminoquinolines (22/27) were more potent than MFQ against multidrug-resistant (MDR) strain C235. In vivo experiments revealed that compound 28 showed clearance with recrudescence at 40 mg/kg/day, while 5/5 mice survived in Thompson test at 160 mg/kg/day
4-Amino-7-chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity
Structurally simplified analogues of dual antimalarial and botulinum neurotoxin serotype A light chain (BoNT/A LC) inhibitor bis-aminoquinoline (1) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of 1. Three of the new compounds are more active than 1 against both indications. Metabolically, the new inhibitors are relatively stable and nontoxic. 12, 14, and 15 are more potent BoNT/A LC inhibitors than 1. Additionally, 15 has excellent in vitro antimalarial efficacy, with IC90 values ranging from 4.45 to 12.11 nM against five Plasmodium falciparum (Pf) strains: W2, D6, C235, C2A, and C2B. The results indicate that the same level of inhibitory efficacy provided by 1 can be retained/exceeded with less structural complexity. 12, 14, and 15 provide new platforms for the development of more potent dual BoNT/A LC and P.f. inhibitors adhering to generally accepted chemical properties associated with the druggability of synthetic molecules.Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3465
Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 mu M and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 mu M). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 +/- 0.37 mu M). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors