Enone– and Chalcone–Chloroquinoline Hybrid Analogues: In Silico Guided Design, Synthesis, Antiplasmodial Activity, in Vitro Metabolism, and Mechanistic Studies

Abstract

Analogs of the previously reported antimalarial hybrid compounds 8b and 12 were proposed with the aim of identifying compounds with improved solubility and retained antimalarial potency. In silico characterization predicted improved solubilities of the analogs, particularly at low pH; they retained acceptable predicted permeability properties, but were predicted to be susceptible to hepatic metabolism. These analogs were synthesized and found to exhibit notable in vitro antimalarial activity. Compounds 25 and 27 were the most active of the analogs. In vitro metabolism studies indicated susceptibility of the analogs to hepatic metabolism. There was also evidence of primary glucuronidation for analogs 24 – 27. Presumed cis - trans isomerism of 12, 22 and 23 under in vitro metabolism assay conditions was also observed, with differences in the nature and rates of metabolism observed between isomers. Biochemical studies strongly suggested that inhibition of hemozoin formation is the primary mechanism of action of these analogs.

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

“…Overall, we can conclude that it is possible to create cinnamic acid/4-aminoquinoline conjugates with promising antimalarial and FP-inhibitory activities, at levels comparable to those of recently reported chalcone-based hybrids [46,47]. Such conjugates constitute promising leads for future development of novel antiplasmodials targeted at blood-stage malaria parasites.…”

Development of Plasmodium falciparum Protease Inhibitors in the Past Decade (2002–2012)

“…Some hybrid drugs, capable of targeting two processes in the malaria life cycle where one of the targets is FP2 inhibition, can fall into the category of non-peptidic small inhibitors [122,123]. For instance, in 2010, Chibale's group identified chalcone-chloroquine hybrid 40 as a promising antimalarial (Fig.…”

“…For instance, in 2010, Chibale's group identified chalcone-chloroquine hybrid 40 as a promising antimalarial (Fig. 30) [122,123]. Compound 40 and related hybrid structures were synthesized and showed to be active against Pf.…”

“…(30). Hybrid drug 40 designed to include FP inhibition ( , -unsaturated system as Michael acceptor) in its mode of antimalarial action [122,123].…”

Synthesis and antimalarial activity of urenyl Bis-chalcone in vitro and in vivo

“…The chalcones have displayed an impressive array of pharmacological activities such as antiprotozoa [8][9][10] , anti-inflammatory 11,12 , antituberculosis agents 13 , immunomodulatory 14 , and anticancer 15 . As our research is devoted to the synthesis of diverse structures as anti-infective agents, we identified the chalcone as good anti-infectious agents [16][17][18] . Keeping this in mind, we designed and synthesized new prototypes by combining both urenyl Bis-acetophenone and substituted benzaldehyde to yield the corresponding Bis-chalcones (Scheme 1) and highlighted their in vitro and in vivo antimalarial activities.…”