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

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

  • Bioorg Med Chem Lett. 2015 Nov 15;25(22):5339-43. doi: 10.1016/j.bmcl.2015.09.033.
Edward Avilés 1,  Jacques Prudhomme 2,  Karine G Le Roch 2,  Scott G Franzblau 3,  Kevin Chandrasena 4,  Alejandro M S Mayer 4,  Abimael D Rodríguez 5
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Puerto Rico, PO Box 23346, U.P.R. Station, San Juan, PR 00931-3346, United States.
  • 2 Department of Cell Biology and Neuroscience, University of California at Riverside, CA 92521, United States.
  • 3 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.
  • 4 Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, United States.
  • 5 Department of Chemistry, University of Puerto Rico, PO Box 23346, U.P.R. Station, San Juan, PR 00931-3346, United States. Electronic address: [email protected].
PMID: 26421992 DOI: 10.1016/j.bmcl.2015.09.033
Abstract

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.

Keywords

Anti-neuroinflammatory activity; Isocyanide; Malaria; Natural product hybridization; Tuberculosis; Ugi multicomponent reaction.

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