Novel naphthyl based 1,2,4-trioxanes: Synthesis and in vivo efficacy in the Plasmodium yoelii nigeriensis in Swiss mice

• Published in: Bioorganic & medicinal chemistry letters 2021-11, Vol.51, p.128372-128372, Article 128372
• Main Authors: Karnatak, Manvika, Hassam, Mohammad, Vanangamudi, Murugesan, Sharma, Siddharth, Kumar Yadav, Dinesh, Singh, Chandan, Puri, Sunil K., Rawat, Varun, Prakash Verma, Ved
• Format: Article
• Language: English
• Subjects: 1,2,4-Trioxane; Animals; Antimalarial Activity; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Multiple - drug effects; Endoperoxide; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Malaria - drug therapy; Malaria - parasitology; Mice; Molecular Structure; Multidrug-Resistant; Parasitic Sensitivity Tests; Photooxygenation; Plasmodium yoelii - drug effects; Structure-Activity Relationship; β-Hydroxyhydroperoxide
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.128372

[Display omitted] A new series of 1,2,4-trioxanes 9a1-a4, 9b1-b4, 10–13 and 9c1-c4 were synthesized and evaluated against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via oral and intramuscular (i.m.) routes. Adamantane-based trioxane 9b4, the most active compound of the series, provided 100% protection to the infected mice at the dose 48 mg/kg × 4 days and 100% clearance of parasitemia at the dose 24 mg/kg × 4 days via oral route. Adamantane-based trioxane 9b4, is twice active than artemisinin. We have also studied the photooxygenation behaviour of allylic alcohols 6a-b (3-(4-alkoxynaphthyl)-but-2-ene-1-ols) and 6c (3-[4-(tert-butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-but-2-en-1-ol). Being behaving as dienes, they furnished corresponding endoperoxides, while behaving as allylic alcohols, they yielded β-hydroxyhydroperoxides. All the endoperoxides (7a-c) and β-hydroxyhydroperoxides (8a-c) have been separately elaborated to the corresponding 1,2,4-trioxanes, except from endoperoxide 7c. It is worthy to note that TBDMS protected naphthoyl endoperoxide 7c unable to deliver 1,2,4-trioxane, which demonstrated the strength of the O-Si bond is not easy to cleave under acidic condition.