Antimalarial Activity of 9a-N Substituted 15-Membered Azalides with Improved in Vitro and in Vivo Activity over Azithromycin

Abstract

Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis.

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

“…31 Nevertheless, various ACQ-based derivatives are being investigated for their antimalarial activity, either since they appear highly active and nontoxic, such as pyrrolizidine-ACQ compounds 32 and aminoquinoline AQ-13, 33 or because of their contribution to the development of SAR, for example, compounds such as 4- N- , 4- S -, or 4- O -alkylaminoquinoline derivatives. 34 Hybrid adducts of various biologically active compounds covalently bonded to the ACQ moiety, 35 such as reversal agents, 36 complexes with Au and Ru, 37 antibiotic azithromycin, 38 2-imidazolidine and ferrocenyl derivatives, 39 and tetraoxanes, 40 are of special interest. Very recently, a breakthrough in the antimalarial field has been achieved: quinolone antimalarials that target the parasite’s liver and blood stages, as well as forms that are crucial to disease transmission, have been reported.…”

In vitro activity of Pheroid vesicles containing antibiotics against Plasmodium falciparum

“…The rapid development of resistance against existing antimalarial compounds poses a problem in the efforts to combat the disease. 4 New chemotherapy strategies are underway [5][6][7][8] but is slow in delivering compounds on the market. In the efforts to address the problem two possible alternative strategies have emerged.…”

Recent advances in malaria drug discovery

“…89 By itself, azithromycin is a slow-acting antimalarial, with a maximum antiparasitic effect occurring only after two cycles of intraerythrocytic development (one cycle of invasion, development, and egress lasts 42–48 h). 89,90 Finding azithromycin analogs with improved activity in mouse models of malaria has been challenging. 90–92 …”

“…89,90 Finding azithromycin analogs with improved activity in mouse models of malaria has been challenging. 90–92 …”