A Concise Total Synthesis of Dehydroantofine and Its Antimalarial Activity against Chloroquine‐Resistant Plasmodium falciparum

Abstract

The total synthesisofd ehydroantofine was achieved by employing an ovel, regioselective, azahetero Diels-Alder reaction of easilya ccessible 3,5-dichloro-2H-1,4-oxazin-2-one with 14 a as ak ey step. Furthermore, it is demonstrated that dehydroantofinei sapromisingc andidate as an ew antimalarial agent in ab iological assay with chloroquine-resistant Plasmodium falciparum.

Synthesis of Densely Substituted Pyridines through 1,2‐Oxazine‐6‐ones Inverse Electron Demand Diels–Alder Reaction

“…In all cases ( 4 h – k ), a single 2,3,4,6‐substituted isomer containing the Ar substituent in the ortho position to the nitrogen atom was obtained. This outcome contrasts, for example, with approach based on 1,4‐oxazinones [19] . The correlation between the electronic properties of the aryl substituent and the reaction yield was dramatic in this case.…”

“…This outcome contrasts, for example, with approach based on 1,4oxazinones. [19] The correlation between the electronic properties of the aryl substituent and the reaction yield was dramatic in this case. Thus, electron-donating thiophene and methoxyphenyl derivatives (4 i and 4 j) were obtained in 86 % and 98 % yield, respectively, in comparison with the phenyl-substituted product 4 h with a yield of 77 %.…”

“…Indeed, easily available 1,3‐, 1,4‐, and 1,5‐oxazinones are known to participate in a number of hDA‐rDA processes, which are well documented in the literature (Scheme 1). [17–22] However, no similar reaction has been previously reported for 1,2‐oxazinones, although they contain a weak N−O bond and could be suited the best. In this paper, we disclose the first example of the introduction of such substrates into the hDA‐rDA tandem (Scheme 1).…”

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

“…Yamasaki and colleagues synthesised dehydroantofine chloride (75) and studied their activity against drug-sensitive PfFCR3 (IC 50 of 0.056 μM) and resistant PfK1 (IC 50 of 0.053 μM) strains. [94] The azatriphenylene core with a pyridinium cation structure was found to be responsible for anti-malarial potential with less cytotoxicity towards animal cells, warranting further in vivo investigations to claim it as a preclinical anti-malarial agent. Giannis and colleagues synthesised and evaluated the anti-malarial activities of C-10 modified non-acetal artemisinin derivative (76) with IC 50 of 0.9 μM against PfNF54 along with cytotoxicity (IC 50 ) of 41.95 μM against acute lymphoblastic leukemia cell lines.…”

“…Yamasaki and colleagues synthesised dehydroantofine chloride ( 75 ) and studied their activity against drug‐sensitive Pf FCR3 (IC 50 of 0.056 μM) and resistant Pf K1 (IC 50 of 0.053 μM) strains [94] . The azatriphenylene core with a pyridinium cation structure was found to be responsible for anti‐malarial potential with less cytotoxicity towards animal cells, warranting further in vivo investigations to claim it as a preclinical anti‐malarial agent.…”