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 najviša postignuta vrednost akridinskih derivata prema ovom serotipu. Adamantil-akridinski derivati su pokazali najveću antimalarijsku aktivnost (IC50 u opsegu 6-9 nM, SI gt 326), pokazujući da je adamantil-grupa bolji nosač farmakofore u poređenju sa steroidnim, prema ovoj indikaciji.

Supplementary data for article: Opsenica, I.; Tot, M.; Gomba, L.; Nuss, J. E.; Sciotti, R. J.; Bavari, S.; Burnett, J. C.; Šolaja, 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), 5860–5871. 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.; Šolaja, 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), 5860–5871. 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

Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria

Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2

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

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

The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease

Botulinum neurotoxins (BoNTs), composed of a family of seven serotypes (categorized A-G), are the deadliest of known biological toxins. The activity of the metalloprotease, light chain (LC) component of the toxins is responsible for causing the life-threatening paralysis associated with the disease botulism. Herein we report significantly more potent analogs of novel, lead BoNT serotype A LC inhibitor 2,5-bis(4-amidinophenyl)thiophene (K-i = 10.881 mu M +/- 0.90 mu M). Specifically, synthetic modifications involved simultaneously replacing the lead inhibitor's terminal bis-amidines with secondary amines and the systematic tethering of 4-amino-7-chloroquinoline substituents to provide derivatives with K-i values ranging from 0.302 mu M (+/- 0.03 mu M) to 0.889 mu M (+/- 0.11 mu M). (C) 2012 Elsevier Masson SAS. All rights reserved.Peer-reviewed manuscript: [http://cherry.chem.bg.ac.rs/handle/123456789/2787

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 (<b>1</b>) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of <b>1</b>. Three of the new compounds are more active than <b>1</b> against both indications. Metabolically, the new inhibitors are relatively stable and nontoxic. <b>12</b>, <b>14</b>, and <b>15</b> are more potent BoNT/A LC inhibitors than <b>1</b>. Additionally, <b>15</b> has excellent in vitro antimalarial efficacy, with IC₉₀ values ranging from 4.45 to 12.11 nM against five Plasmodium falciparum (<i>P.f.</i>) strains: W2, D6, C235, C2A, and C2B. The results indicate that the same level of inhibitory efficacy provided by <b>1</b> can be retained/exceeded with less structural complexity. <b>12</b>, <b>14</b>, and <b>15</b> provide new platforms for the development of more potent dual BoNT/A LC and <i>P.f.</i> inhibitors adhering to generally accepted chemical properties associated with the druggability of synthetic molecules

Second Generation Steroidal 4‑Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and <i>P. falciparum</i> Malaria

Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC₅₀ values for such derivatives ranged from 0.81 to 2.27 μM). Two additional subclasses were prepared: bis­(steroidal)-4,7-ACQ derivatives and bis­(4,7-ACQ)­cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the <i>K</i>_i of compound <b>67</b> is 0.10 μM). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds’ in vitro potencies. In addition to specific residue contacts, coordination of the enzyme’s catalytic zinc and expulsion of the enzyme’s catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC₉₀ activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2

Characterization of Ebola Virus Disease (EVD) in Rhesus Monkeys for Development of EVD Therapeutics

Recent Ebola virus (EBOV) outbreaks in West Africa and the Democratic Republic of the Congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of EBOV disease (EVD). Until recently, when successes were achieved in characterizing the efficacy of multiple experimental EVD therapeutics in humans, the only feasible way to obtain data regarding potential clinical benefits of candidate therapeutics was by conducting well-controlled animal studies. Nonclinical studies are likely to continue to be important tools for screening and development of new candidates with improved pharmacological properties. Here, we describe a natural history study to characterize the time course and order of progression of the disease manifestations of EVD in rhesus monkeys. In 12 rhesus monkeys exposed by the intramuscular route to 1000 plaque-forming units of EBOV, multiple endpoints were monitored for 28 days following exposure. The disease progressed rapidly with mortality events occurring 7&ndash;10 days after exposure. Key disease manifestations observed consistently across the infected animals included, but were not limited to, viremia, fever, systemic inflammation, coagulopathy, lymphocytolysis, renal tubular necrosis with mineralization, and hepatocellular degeneration and necrosis