Structure–Activity Relationship of Antischistosomal Ozonide Carboxylic Acids

Abstract

Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomesanother hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure–activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.

Peroxide Antimalarial Drugs Target Redox Homeostasis in Plasmodium falciparum Infected Red Blood Cells

“…Step 1 : to a solution of cis -6-oxoadamantane-2-spiro-3′-8′-(4-hydroxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane 52 (500 mg, 1.35 mmol) in dry DME (25 mL) were added powdered NaOH (324 mg, 8.01 mmol) and Bu 4 NHSO 4 (93 mg, 0.50 mmol). The resulting mixture was stirred at room temperature (rt) for 30 min before the addition of N -(2-chloroethyl)morpholine hydrochloride (415 mg, 2.22 mmol).…”

“…Found: C, 70.00; H, 7.47; N, 2.77. Step 2 : following the method of Wu et al, 52 a one-pot reductive amination/acylation of cis- 6-oxoadamantane-2-spiro-3′-8′-[4-(2-morpholinoethoxy)phenyl]-1′,2′,4′-trioxaspiro[4.5]decane (430 mg, 0.89 mmol) afforded the free base of OZ747 (170 mg, 34%). Step 3 : to a solution of the free base of OZ747 (170 mg, 0.30 mmol) in EA (5 mL) was added dropwise a solution of methanesulfonic acid (58 mg, 0.60 mmol) in diethyl ether (1 mL).…”

Antimalarial and anticancer properties of artesunate and other artemisinins: current development

“…Besides antimalarial, anticancer, and antiviral properties, artemisinins are also effective against schistosomes–hemoglobin degrading pathogen [ 75 ], ocular diseases [ 76 ], and in inflammations [ 77 ].…”

Tribute to Jonathan Vennerstrom

“…In collaboration with researchers at the Swiss Tropical and Public Health Institute and Monash University, Jonathan and coworkers discovered his synthetic ozonides were also endowed with potent trematocidal properties showing activity against various Schistosoma species as well as several other important trematodes known to cause disease in the intestine and liver. 5 In parallel efforts, his laboratories have explored a novel series of aryl hydantoins 6 and diarylureas 7 with impressive antischistosomal activity. In addition to his foundational work on malaria and schistosomiasis, Jonathan has developed a novel class of diimidazolines for the treatment of African trypanosomiasis with an improved safety profile compared to the current standard of care pentamidine for the first stage of the disease.…”

“…Jonathan’s multifaceted research program is also focused on schistosomiasis, a disease caused by freshwater parasitic trematodes afflicting over 200 million people annually. In collaboration with researchers at the Swiss Tropical and Public Health Institute and Monash University, Jonathan and co-workers discovered his synthetic ozonides were also endowed with potent trematocidal properties showing activity against various Schistosoma species as well as several other important trematodes known to cause disease in the intestine and liver . In parallel efforts, his laboratories have explored a novel series of aryl hydantoins and diarylureas with impressive antischistosomal activity.…”