title: Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold.
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.
authors.affiliation: Department of Chemistry, University of Puerto Rico, PO Box 23346, U.P.R. Station, San Juan, PR 00931-3346, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Avilés
authors.affiliation: Department of Cell Biology and Neuroscience, University of California at Riverside, CA 92521, United States.
authors.forename: Jacques
authors.initials: J
authors.lastname: Prudhomme
authors.affiliation: Department of Cell Biology and Neuroscience, University of California at Riverside, CA 92521, United States.
authors.forename: Karine G
authors.initials: KG
authors.lastname: Le Roch
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chandrasena
authors.affiliation: Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, United States.
authors.forename: Alejandro M S
authors.initials: AM
authors.lastname: Mayer
authors.affiliation: Department of Chemistry, University of Puerto Rico, PO Box 23346, U.P.R. Station, San Juan, PR 00931-3346, United States. Electronic address: abimael.rodriguez1@upr.edu.
authors.forename: Abimael D
authors.initials: AD
authors.lastname: Rodríguez
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003486:Cyanides / Q000138:chemical synthesis* / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000588:Amines; D000893:Anti-Inflammatory Agents; D003486:Cyanides; D011804:Quinolines; D054852:Small Molecule Libraries; C037219:quinoline
keywords: Anti-neuroinflammatory activity; Isocyanide; Malaria; Natural product hybridization; Tuberculosis; Ugi multicomponent reaction