Insertion of Isocyanides into N-Si Bonds: Multicomponent Reactions with Azines Leading to Potent Antiparasitic Compounds.
Trimethylsilyl chloride is an efficient activating agent for azines in isocyanide-based reactions, which then proceed through a key insertion of the isocyanide into a N-Si bond. The reaction is initiated by N activation of the azine, followed by nucleophilic attack of an isocyanide in a Reissert-type process. Finally, a second equivalent of the same or a different isocyanide inserts into the N-Si bond leading to the final adduct. The use of distinct nucleophiles leads to a variety of α-substituted dihydroazines after a selective cascade process. Based on computational studies, a mechanistic hypothesis for the course of these reactions was proposed. The resulting products exhibit significant activity against Trypanosoma brucei and T. cruzi, featuring favorable drug-like properties and safety profiles.
Departamento de Química, Universidad de Guanajuato, Noria Alta S/N, CP 36050, Guanajuato, Gto., Mexico.
Kranti G
KG
Kishore
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona and Barcelona Science Park, Baldiri Reixac 10-12, 08028, Barcelona, Spain.
Ouldouz
O
Ghashghaei
Departament de Nutrició, Ciència dels Aliments i Gastronomia, Facultat de Farmàcia, and IBUB, Universitat de Barcelona, Prat de la Riba 171, 08921, Santa Coloma de Gramenet, Spain.
Carolina
0000-0002-0944-9053
C
Estarellas
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona and Barcelona Science Park, Baldiri Reixac 10-12, 08028, Barcelona, Spain.
M Mar
MM
Mestre
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona and Barcelona Science Park, Baldiri Reixac 10-12, 08028, Barcelona, Spain.
Cristina
C
Monturiol
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona and Barcelona Science Park, Baldiri Reixac 10-12, 08028, Barcelona, Spain.
Nicola
N
Kielland
Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
John M
0000-0003-4305-5258
JM
Kelly
Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
Amanda Fortes
AF
Francisco
Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
Shiromani
S
Jayawardhana
Laboratori de Química Farmacèutica, Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain.
Diego
0000-0002-8140-8555
D
Muñoz-Torrero
Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
Belén
0000-0001-5801-1704
B
Pérez
Departament de Nutrició, Ciència dels Aliments i Gastronomia, Facultat de Farmàcia, and IBUB, Universitat de Barcelona, Prat de la Riba 171, 08921, Santa Coloma de Gramenet, Spain.
F Javier
0000-0002-8049-3567
FJ
Luque
Departamento de Química, Universidad de Guanajuato, Noria Alta S/N, CP 36050, Guanajuato, Gto., Mexico. rociogm@ugto.mx.
Rocío
0000-0002-2062-5468
R
Gámez-Montaño
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona and Barcelona Science Park, Baldiri Reixac 10-12, 08028, Barcelona, Spain. rlavilla@pcb.ub.es.
Rodolfo
0000-0001-9159-6089
R
Lavilla
D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003486:Cyanides / Q000737:chemistry*; D006834:Hydrazines / Q000737:chemistry*; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D021261:Parasitic Sensitivity Tests; D012825:Silicon / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000187:drug effects*
D000977:Antiparasitic Agents; D003486:Cyanides; D006834:Hydrazines; D009584:Nitrogen; D012825:Silicon
azines; isocyanides; multicomponent reactions; silicon; trypanosomiasis