Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold

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• 作者：Edward Avilé ; s^a ; Jacques Prudhomme^b ; Karine G. Le Roch^b ; Scott G. Franzblau^c ; Kevin Chandrasena^d ; Alejandro M.S. Mayer^d ; Abimael D. Rodrí ; guez^a ; ^{abimael.rodriguez1@upr.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Tuberculosis ; Malaria ; Anti-neuroinflammatory activity ; Ugi multicomponent reaction ; Isocyanide ; Natural product hybridization
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：25
• 期：22
• 页码：5339-5343
• 全文大小：1519 K

文摘

A mixture-based combinatorial library of five Ugi adducts (4–8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-component reactions (U-4C-3CR). The novel α-acylamino amides obtained were evaluated for their antiinfective potential against laboratory strains of Mycobacterium tuberculosis H₃₇Rv and chloroquine-susceptible 3D7 Plasmodium falciparum. Interestingly, compounds 4–8 displayed potent in vitro antiparasitic activity with higher cytotoxicity in comparison to their diisocyanide precursor 3, with the best compound exhibiting an IC₅₀ value of 3.6 nM. Additionally, these natural product inspired hybrids potently inhibited in vitro thromboxane B₂ (TXB₂) and superoxide anion (O₂⁻) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity.