Synthesis and Antimalarial Effects of Phenothiazine Inhibitors of a Plasmodium falciparum Cysteine Protease

Abstract

Acridinediones have previously been shown to have potent antimalarial activity. A series of sulfur isosteres of acridinediones have been synthesized and evaluated for their inhibition of the Plasmodium falciparum cysteine protease falcipain and for their antimalarial activity. A number of these phenothiazines inhibited falcipain and demonstrated activity against cultured P. falciparum parasites at low micromolar concentrations. We propose that the compounds exerted their antimalarial effects by two mechanisms, one of which involves the inhibition of falcipain and a consequent block in parasite degradation of hemoglobin. These compounds and related phenothiazines are worthy of further study as potential antimalarial agents.

Novel oxazine skeletons as potential antiplasmodial active ingredients: Synthesis, in vitro and in vivo biology of some oxazine entities produced via cyclization of novel chalcone intermediates

“…Prepared by the above method from 2 (8 mmol, 1.1 g) and acetophenone (8 Chloroquinolin-3-yl)-1-p-tolyl prop-2-en-1-one (3d Chloroquinolin-3-yl)-1-(2-bromophenyl) Chlroquinlin-3-yl)-1-(3-nitrophenyl) prop-2-en-1-one (3h) Prepared by above method from 2 (8 mmol, 1.1 g) and 3-nitroacetophenone (8 mmol, 1.75 g); yield: 1.61 g, 60%, R f = 0.54 in EtOAc/hexane, 4:6; pale yellow solid. Chloroquinolin-3-yl)-1-(3,4,5-trimethoxyphenyl) …”

“…P. falciparum is responsible for the most deaths and it has developed resistance against almost all the available drugs 6 so far in the market. The search for novel antimalarial drugs against specific parasitic targets is thus an immense priority 7,8 for the medicinal chemists all over the world for the sake of humanity. The potential antimalarial activity of chalcones has generated a great interest.…”

A green development of Bernthsen 9-substituted acridine synthesis in the absence of solvent catalyzed byp-toluenesulphonic acid (p-TSA)

“…Acridines represent an important class of nitrogen heterocycles (1,2) having several significant properties such as pigment and dye properties (3Á5), photochemical/physical properties (6Á8), electrochemical properties (9), potent anti-malarial activity (10), anticancer activity (11Á16), 1 antifungal activity (17Á 20), etc. Natural and synthetic acridines and their derivatives are effective DNA and RNA-binding compounds (21Á24) owing to their intercalation abilities as well as being a lipophilic carrier molecule.…”

Design, synthesis and evaluation of novel quinolinyl chalcones as antibacterial agents

“…[3][4][5][6] Quinoline-based fused heterocyclic systems are found as potential anticancer agents 7 and have antimalarial activities. 8 Pyrimidine derivatives…”

“…After cooling, the resulting solid was filtered, dried and recrystallized from ethanol to obtain compound 4, yield 68%, as yellowish white solid. Mp 178 o C. 1-(4-aminophenyl)-3-(2-morpholino-7-methylquinolin-3-yl)-2-propen-1-one (5). To a solution of 4-aminoacetophenone (0.1 mol 13.5 g), 4 (0.1 mo 20% NaOH solution (20 ml) was stirred for 0.5 h at room temperature and left overnight.…”