New 9-aminoacridine derivatives as inhibitors of Botulinum neurotoxins and P. falciparum malaria

Abstract

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 (IC 50 = 6-9 nM, SI > 326), indicating that an adamantyl group is a better carrier than a steroidal motif for this indication.

Acridine‐containing RuII, OsII, RhIII and IrIII Half‐Sandwich Complexes: Synthesis, Structure and Antiproliferative Activity

“…All reactions were carried out in air unless otherwise stated. The precursors, Ru( p ‐cym)Cl 2 ] 2, [Os( p ‐cym)Cl 2 ] 2, [RhCp*Cl 2 ] 2, [IrCp*Cl 2 ] 2 and N 1 ‐(6‐chloro‐2‐methoxyacridin‐9‐yl)ethane‐1,2‐diamine ( L1 ), were synthesized using literature methods. 1 H NMR, 13 C{ 1 H} NMR and 31 P{ 1 H} NMR spectra were recorded on a Bruker Ultrashield 400 ( 1 H NMR 400.17 MHz, 13 C{ 1 H} NMR 101.02 MHz and 13 P{ 1 H} NMR 161.99 MHz) spectrometer and chemical shifts are reported using tetramethylsilane and H 3 PO 4 (for 31 P{ 1 H} NMR) spectra as the internal standard.…”

“…N 1 ‐(6‐chloro‐2‐methoxyacridin‐9‐yl)ethane‐1,2‐diamine ( L1 ) was synthesized using the procedure described by Tot et al . 6,9‐Dichloro‐2‐methoxyacridine was added to excess ethylene diamine and refluxed for 20 hours (Scheme ).…”

A new look at 9‐substituted acridines with various biological activities

“…Steroidal and adamantane aminoacridine derivatives were prepared and their antimalarial activity was investigated. The adamantane acridines were found to be the most potent derivatives against malaria, indicating that an adamantyl group is a better carrier than a steroidal motif in this respect (Tot et al, 2013). A summary of the most efficient 9-aminoacridines with topoisomerase I/II and antimalarial and antibacterial activities is given in Figure 15.…”

Acridine-Based Antimalarials—From the Very First Synthetic Antimalarial to Recent Developments

“…Based on reports concerning the good inhibitory activity of steroidal 4-aminoquinolines, and adamantyl-aminoquinolines [ 52 ], Tot et al [ 53 ] expanded their work towards the synthesis and in vitro antimalarial activity of news 9-aminoalkylaminoacridine derivatives possessing steroid and adamantane carriers ( 34 and 35, and 36 , respectively; Figure 23 ). Compound 36 , an adamantyl derivative, presented an antimalarial activity comparable to that of artemisinin and better than CQ against the Pf CQS D6, CQR W2 and multi-drug resistant TM91C235 strains ( 36: IC 50 (W2) = 8.6 nM, IC 50 (D6) = 9.3 nM, IC 50 (TM91C235) = 5.8 nM; Artemisinin: IC 50 (W2) = 6.70 nM, IC 50 (D6) = 9.00 nM, IC 50 (TM91C235) = 13.40 nM; CQ : IC 50 (W2) = 456.20 nM, IC 50 (D6) = 12.27 nM, IC 50 (TM91C235) = 138.82 nM).…”

“…Compound 36 , an adamantyl derivative, presented an antimalarial activity comparable to that of artemisinin and better than CQ against the Pf CQS D6, CQR W2 and multi-drug resistant TM91C235 strains ( 36: IC 50 (W2) = 8.6 nM, IC 50 (D6) = 9.3 nM, IC 50 (TM91C235) = 5.8 nM; Artemisinin: IC 50 (W2) = 6.70 nM, IC 50 (D6) = 9.00 nM, IC 50 (TM91C235) = 13.40 nM; CQ : IC 50 (W2) = 456.20 nM, IC 50 (D6) = 12.27 nM, IC 50 (TM91C235) = 138.82 nM). Compound cytotoxicity was evaluated in the human liver carcinoma cell line HepG2, and compound 36 exhibited the best selectivity index (SI(W2) = 352; SI(D6) = 326; SI(TM91C235) = 522) [ 53 ].…”