The Synthesis of Waltherione F and Its Analogues with Modifications at the 2‐ and 3‐Positions as Potential Antitrypanosomal Agents

Abstract

Chagas disease also know as AmericanT rypanosomiasis (AT) is at ropical parasitic disease endemici nS outh America, is caused by Trypanosoma cruzi,w hichi st ransmitted by the blood-sucking insect vectors called triatomine bugs. Quinoline alkaloids from the root extract of Waltheria indica are known to possess antitrypanosomal activity. Waltherione F, one of those alkaloids, was synthesised in 5steps in 11 %o verall yield. We report here the first X-ray crystallographic confirmation of the structureo fW altherione F 3.Akey step in the sequence utilisedt he Conrad-Limpach synthesis for the formation of the quinolin-4(1H)-oner ing system. Our synthetic strategy was designed to enablet he modification of the 2-and 3-positions of the scaffold, allowing the generation of ad iverse libraryo fa nalogues to support our on-going medicinal chemistry program that is looking for new agents to tackle this devastating disease.

Synthesis, Fungicidal Activity, and Mechanism of Action of Pyrazole Amide and Ester Derivatives Based on Natural Products l-Serine and Waltherione Alkaloids

“…The development of new green fungicides based on the structural optimization of natural products can effectively solve the problems of low safety and high pathogen resistance of traditional fungicides, which is a hot research field of green agrochemicals. − Waltherione alkaloids are 4-quinolone compounds isolated from traditional Chinese herbal medicine Waltheria indica L. of the Sterculiaceae family. To date, 20 waltherione alkaloids have been successfully isolated, including waltherione A-Q, antidesmone, 8-deoxoantidesmone, and vanessine (Figure ), − and were found successively to have antiviral, antitumor, antitrypanosomal, bactericidal, fungicidal, nematicidal, and other biological activities. − …”

Hypervalent Iodine(III)-Promoted C3–H Regioselective Halogenation of 4-Quinolones under Mild Conditions

“…Hence, all of the halogenation reactions could be easily amplified in water with comparable yields to the small amounts of reactions carried out in MeOH (Table , entries 2e and 3a ; Table , entry 4a ). To the best of our knowledge, 3-halo-4-quinlones could be easily furnished via Suzuki–Miyaura cross coupling , or functional group transformation reactions ,, to elaborate the medicinal importance of 4-quinolones, implying the potential application value of this method.…”

“… 24 Furthermore, Chu’s group disclosed an electrochemical method for trifluoromethylation of 4-quinolones via a free radical mechanism ( Scheme 1 b). 25 Hitherto, the direct halogenation methods of 4-quinolones have been reported mainly using N -halogen succinimide (NXS), 11d , 26 Br 2 , 27 I 2 , 28 pyridinium tribromideor, 28 isocyanuric chloride, 11a and other toxic halogenating sources under harsh reaction conditions ( Scheme 1 c), except for a photoredox-catalyzed halogenation of 4-quinolones reported by Ritu et al . very recently, which uses eosin Y or rose bengal as the halogen source and photosensitizer ( Scheme 1 c).…”

Access to 2-Alkyl/Aryl-4-(1H)-Quinolones via Orthogonal “NH3” Insertion into o-Haloaryl Ynones: Total Synthesis of Bioactive Pseudanes, Graveoline, Graveolinine, and Waltherione F

“…In addition, an -OMe group ortho to the carbonyl was introduced in two steps involving NBS-mediated bromination and CuI-catalyzed S N Ar type displacement with NaOMe to deliver waltherione F 17 (six steps, 33% overall yield) and the value was found to be spectroscopically identical with the values reported for the natural product (see the Supporting Information). ,, …”

“…3c Waltherione F is notable for exhibiting antitrypanosomal activity against Trypanosoma cruzi, a parasite that causes Chagas disease. To date, two total syntheses of natural product 17 have been reported by Larghi et al 18 utilizing Suzuki− Miyaura coupling and microwave-assisted cyclization as the key reactions (seven steps, 31% overall yield) and by Cox et al 19 employing Conrad−Limpach synthesis as a key step (five steps, 11% overall yield).…”