Rubén M. Carballo

A new catalytic Prins cyclization leading to oxa- and azacycles.

A new Prins cyclization process that builds up one carbon-carbon bond, one heteroatom-carbon bond, and one halogen-carbon bond, (in an oxa- and azacycle) relies on an iron catalyst system formed from Fe(acac)3 and trimethylsilyl halide. The method displays a broad substrate scope and is economical, environmentally friendly, and experimentally simple. This catalytic method permits the construction of chloro, bromo and iodo heterocycles, by the suitable combination of iron(III) source, the corresponding trimethylsilyl halide and the solvent, in high yields.

Iron(III)-Catalyzed Consecutive Aza-Cope−Mannich Cyclization: Synthesis of trans-3,5-Dialkyl Pyrrolidines and 3,5-Dialkyl-2,5-dihydro-1H-pyrroles

An efficient alkene aza-Cope-Mannich cyclization between 2-hydroxy homoallyl tosylamine and aldehydes in the presence of iron(III) salts to obtain 3-alkyl-1-tosyl pyrrolidines in good yields is described. The process is based on the consecutive generation of a γ-unsaturated iminium ion, 2-azonia-[3,3]-sigmatropic rearrangement, and further intramolecular Mannich reaction. Iron(III) salts are also shown to be excellent catalysts for the new aza-Cope-Mannich cyclization using 2-hydroxy homopropargyl tosylamine.

β′-Hydroxy-α,β-unsaturated ketones: A new pharmacophore for the design of anticancer drugs. Part 2.†

Novel antiproliferative β′‐acyloxy‐α,β‐unsaturated ketones were obtained by means of an iron(III)‐catalyzed multicomponent domino process (ABB′ 3CR). The most active derivatives displayed GI50 values in the range of 0.5–3.9 μM against a panel of representative human solid tumor cell lines: A2780, SW1573, HBL‐100, T‐47D and WiDr. Analysis of cells following 24 h exposure to these drugs showed cell cycle arrest in the S and G2/M phase, in a dose‐dependent manner. Our data indicate that the β′‐acyloxy‐α,β‐unsaturated ketones cause permanent damage to the cells and induce apoptosis.

Diversifying Complexity by Domino Benzannulation of Polycyclic Natural Products

Herein we describe a salicylaldehyde-annulation reaction as a plug and play toolkit to diversify the complexity of naturally occurring ketones. The protocol entails the transformation of the polycyclic natural ketone into its propargyl vinyl ether derivative (two synthetic steps) and its microwave-assisted imidazole-catalyzed domino rearrangement to generate the salicylaldehyde ring. This annexed unit allows further synthetic transformations: e.g., the installation of a pharmacophore module to generate natural product-pharmacophore hybrids endowed with unknown biological (pharmaceutical) annotations.

2-Amino-4-arylthiazole Derivatives as Anti-giardial Agents: Synthesis, Biological Evaluation and QSAR Studies

4-Phenyl-thiazol-2-ylamine (1a): Straw color solid: mp 148°C. 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J = 7.4 Hz, 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 7.05 (s, 2H), 6.99 (s, 1H). 13C NMR (CDCl3, 100 MHz) δ 168.3 (C), 149.9 (C), 134.9 (C), 128.6 (2CH), 127.3 (C), 125.6 (2CH), 101.6 (CH). HRMS (EI, 70 eV) Calcd for C9H8N2S [M]+: 176.0408. Found: 176.0409. Yield: 88%. 4-(4-Chloro-phenyl)-thiazol-2-ylamine (1b): Straw color solid: mp 165°C. 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.11 (s, 1H). 13C NMR (CDCl3, 100 MHz) δ 168.9 (C), 146.3 (C), 132.5 (C), 132.2 (C), 128.9 (2CH), 127.5 (2CH), 102.8 (CH). HRMS (EI, 70 eV) Calcd for C9H7N2SCl [M]+: 210.0018. Found: 210.0007. Yield: 91%. 4-(4-Bromo-phenyl)-thiazol-2-ylamine (1c): Straw color solid: mp 179°C. 1H NMR (CDCl3, 400 MHz) δ 7.73 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.10 (s, 2H), 7.07 (s, 1H). 13C NMR (CDCl3, 100 MHz) δ 168.5 (C), 148.7 (C), 134.2 (C), 131.5 (2CH), 127.7 (2CH), 120.2 (C), 102.2 (CH). HRMS (EI, 70 eV) Calcd for C9H7N2SBr [M]+: 255.9493. Found: 255.9476. Yield: 99%. 4-(4-Nitro-phenyl)-thiazol-2-ylamine (1d): Orange solid: mp 286°C.1H NMR (CDCl3, 400 MHz) δ 8.22 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H), 7.40 (s, 1H), 7.23 (s, 2H). 13C NMR (CDCl3, 100 MHz) δ 168.7 (C), 147.9 (C), 146.0 (C), 140.9 (C), 126.4 (2CH), 124.2 (2CH), 106.7 (CH). HRMS (EI, 70 eV) Calcd for C9H7N3O2S [M]+: 221.0259. Found: 221.0249. Yield: 99%. 4-Tolyl-thiazol-2-ylamine (1e): Yellow solid: mp 121°C. 1H NMR (CDCl3, 400 MHz) δ 7.67 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.05 (s, 2H), 6.89 (s, 1H), 2.88 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 168.3 (C), 150.0 (C), 136.5 (C), 132.4 (C), 129.2 (2CH), 125.3 (2CH), 100.7 (CH), 20.9 (CH3). HRMS (EI, 70 eV) Calcd for C10H10N2S [M]+: 190.0565. Found: 190.0565. Yield: 80%. 4-(4-Methoxy-phenyl)-thiazol-2-ylamine (1f): Yellow solid: mp 197°C. 1H NMR (CDCl3, 400 MHz) δ 7.67 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 3.78 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 169.4 (C), 159.5 (C), 144.1 (C), 127.3 (2CH), 124.5 (C), 114.3 (2CH), 100.2 (CH), 55.4 (CH3). HRMS (EI, 70 eV) Calcd for C10H10N2OS [M]+: 206.0514. Found: 206.0520. Yield: 80%. 4-(2-Amino-thiazol-4-yl)-phenol (1g): Yellow solid: mp 179°C. 1H NMR (CDCl3, 400 MHz) δ 9.54 (s, 1H), 7.59 (d, J = 8.6 Hz, 2H), 6.98 (s, 2H), 6.74 (d, J = 8.4 Hz, 2H), 6.71 (s, 1H). 13C NMR (CDCl3, 100 MHz) δ 168.2 (C), 156.9 (C), 150.2 (C), 127.1 (2CH), 126.5 (C), 115.3 (2CH), 98.6 (CH). HRMS (EI, 70 eV) Calcd for C9H8N2OS [M]+: 192.0357. Found: 192.0370. Yield: 62%. *Corresponding author: Gonzalo J. Mena-Rejón: Laboratorio de Química Farmacéutica, Facultad de Química, Universidad Autónoma de Yucatán, Calle 41 No. 421, Col. Industrial, C.P. 97150 Mérida, Yucatán, México, E-mail: mrejon@uady.mx Raul Mocelo-Castell: Facultad de Química, Universidad de La Habana, Zapata s/n entre G y Carlitos Aguirre, Vedado, Plaza de la Revolución, CP 1040 Ciudad de La Habana, Cuba Carlos Villanueva-Novelo, David Cáceres-Castillo, Ruben M. Carballo, Ramiro F. Quijano-Quiñones, Mariana Quesadas-Rojas, Zulema Cantillo-Ciau: Laboratorio de Química Farmacéutica, Facultad de Química, Universidad Autónoma de Yucatán, Calle 41 No. 421, Col. Industrial, C.P. 97150 Mérida, Yucatán, México Cedillo-Rivera, Rosa E. Moo-Puc: Unidad de Investigación Médica Yucatán, Unidad Médica de Alta Especialidad, Centro Médico Ignacio García Téllez IMSS, Calle 41, N. 439, Col. Industrial, Mérida, Yucatán, 97150 México Laila M. Moujir: Departamento de Microbiología y Biología Celular, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 2, 38206, Tenerife, Islas Canarias, España.A series of seven 2-amino-4-arylthiazoles were prepared following Hantzsch’s modified method under microwave irradiation. A set of 50 derivatives was obtained and the in vitro activity against Giardia intestinalis was evaluated. The results on the biological activity revealed that, in general, the N-(5-bromo-4-arylthiazol-2-yl)-acetamide scaffold showed high bioactivity. In particular, compounds 6e (IC50 = 0.39 μM) and 6b (IC50 = 0.87 μM) were found to be more potent than the positive control metronidazole. Citoxicity and acute toxicity tests performed showed low toxicity and high selectivity of the most active compounds (6e SI = 139, 6b SI = 52.3). A QSAR analysis was applied to a data set of 37 obtained 2-amino-4-arylthiazoles derivatives and the best model described a strongly correlation between the anti-giardiasic activity and molecular descriptors as E2M, RDF115m, F10, MATS6v, and Hypnotic-80, with high statistical quality. This finding indicates that N-substituted aminothiazole scaffold should be investigated for the development of highly selective anti-giardial agent.Abstract A series of seven 2-amino-4-arylthiazoles were prepared following Hantzsch’s modified method under microwave irradiation. A set of 50 derivatives was obtained and the in vitro activity against Giardia intestinalis was evaluated. The results on the biological activity revealed that, in general, the N-(5-bromo-4-aryl-thiazol-2-yl)-acetamide scaffold showed high bioactivity. In particular, compounds 6e (IC50 = 0.39 μM) and 6b (IC50 = 0.87 μM) were found to be more potent than the positive control metronidazole. Citoxicity and acute toxicity tests performed showed low toxicity and high selectivity of the most active compounds (6e SI = 139, 6b SI = 52.3). A QSAR analysis was applied to a data set of 37 obtained 2-amino-4-arylthiazoles derivatives and the best model described a strongly correlation between the anti-giardiasic activity and molecular descriptors as E2M, RDF115m, F10, MATS6v, and Hypnotic-80, with high statistical quality. This finding indicates that N-substituted aminothiazole scaffold should be investigated for the development of highly selective anti-giardial agent. Graphical Abstract