A high-order multicomponent reaction involving a six-component reaction to obtain the novel linked 1,5-disubstituted tetrazole-1,2,3-triazole hybrids in low to moderate yield is described. This one-pot reaction is carried out under a cascade process consisting of three sequential reactions: Ugi-azide, bimolecular nucleophilic substitution (SN2), and copper-catalyzed alkyne–azide reaction (CuAAC), with high atom and step-economy due the formation of six new bonds (one C-C, four C-N, and one N-N). Thus, the protocol developed offers operational simplicity, mild reaction conditions, and structural diversity. Finally, to evaluate the antitumoral potential of the synthetized molecules, a proliferation study was performed in the breast cancer (BC) derived cell line MCF-7. The hybrid compounds showed several degrees of cell proliferation inhibition with a remarkable effect in those compounds with cyclohexane and halogens in their structures. These compounds represent potential drug candidates for breast cancer treatment. However, additionally assays are needed to elucidate their complete effect over the cellular hallmarks of cancer.

TABLE OF CONTENTS General Information S1General procedure for compounds 16a-l (GP1) S2Synthesis and NMR spectra of the products 16a-l S2-S19General procedure for compounds 17a-m (GP2) S20Synthesis and NMR spectra of the products 17a-m S20-S39 General informationReagents and solvents were purchased from commercial sources and used without further purification. NMR spectra were recorded on a Bruker Fourier (300 Mhz), Bruker Avance I (400 Mhz) and on a Mercury (400 Mhz). Chemical shifts were reported as δ values (ppm). Coupling constants J are reported in Hertz (Hz). Internal reference for NMR spectra is in respect to TMS at 0.0 ppm. Multiplicities are reported, using the standard abbreviations, as follows: singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublets (dd), broad signal (bs), doublet of triplets (dt), triplet of doublets (td), quartet of doublets (qd), multiplet (m), apparent triplet (at).NMR spectra were analyzed using the MestreNova software (version 6.0.2-5475). IR spectra were recorded on a Thermo Scientific NICOLET iS10 by ATR method using neat compounds. The wavelengths are reported in reciprocal centimeters ( /cm -1 ). HRMS spectra were acquired on a Bruker MicroTOF-II spectrometer. Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. Reaction progress was monitored by thin layer chromatography (TLC) using silica gel 60 F254 from Merck and the spots were visualized under UV light at 254 or 365 nm. Column chromatography was performed using silica gel (230-400 mesh). Chemical names and drawings were obtained using ChemDraw Professional (version 15.0.0.106). S2General procedure for compounds 16a-l (GP1)Propargylamine (1.0 equiv.) and aldehyde (1.0 equiv.) were placed on a 5 mL round bottom flask and reacted for 5 min, then isocyanide (1.0 equiv.) and TMSN3 (1.3 equiv.) were sequentially added. The reaction mixture was stirred at room temperature for 24 h. Then, the reaction crude was purified by flash column chromatography with Hexane:EtOAc 7:3 (v/v) to afford the 1,5-DS-T 16a-l.Based on the GP1, propargylamine (11.6 µL, 0.18 mmol), 2-fluorobenzaldehyde (19.0 µL, 0.18 mmol), TMSN3(30.9 µL, 0.23 mmol) and tert-butyl isocyanide (20.5 µL, 0.18 mmol) were used and 16a was obtained as a yellow oil (yield 47.9 mg, 92%).

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