Ramiro Quijano-Quiñones

The Rotational Barrier in Ethane: A Molecular Orbital Study

The energy change on each Occupied Molecular Orbital as a function of rotation about the C-C bond in ethane was studied using the B3LYP, mPWB95 functional and MP2 methods with different basis sets. Also, the effect of the ZPE on rotational barrier was analyzed. We have found that σ and π energies contribution stabilize a staggered conformation. The σs molecular orbital stabilizes the staggered conformation while the stabilizes the eclipsed conformation and destabilize the staggered conformation. The πz and molecular orbitals stabilize both the eclipsed and staggered conformations, which are destabilized by the πv and molecular orbitals. The results show that the method of calculation has the effect of changing the behavior of the energy change in each Occupied Molecular Orbital energy as a function of the angle of rotation about the C–C bond in ethane. Finally, we found that if the molecular orbital energy contribution is deleted from the rotational energy, an inversion in conformational preference occurs.

Cytotoxic diterpenes from roots of Crossopetalum gaumeri, a Celastraceae species from Yucatan Peninsula

Four new diterpenes, crossogumerins A-D (1-4) along with six known ones (5-10) were isolated from the root bark of Crossopetalum gaumeri, an endemic medicinal plant from the Yucatan Peninsula. Their structures were elucidated on the basis of 1D and 2D NMR techniques, including HMQC, HMBC, and ROESY experiments. Compounds 1-5, 8-10 were evaluated for cytotoxicity against HeLa (carcinoma of the cervix) and Hep-2 (lung carcinoma) human tumor cells lines and against normal Vero cells (African green monkey kidney) in lag and log phase of growth. Podocarpane diterpenes, crossogumerin B (2) and nimbiol (10), exhibited the highest activity against HeLa cells (IC50 values of 3.1 and 8.1 μM, respectively), but also selectivity on Vero cells (SI 22.6 and 7.5, respectively). The preliminary SAR studies suggest that an epoxy moiety in ring B and a hydrogen bond-donor group strategically positioned in the diterpene core are important requirements for cytotoxicity and selectivity.

Biogenesis of Triterpene Dimers from Orthoquinones Related to Quinonemethides: Theoretical Study on the Reaction Mechanism

The biogenetic origin of triterpene dimers from the Celastraceae family has been proposed as assisted hetero-Diels-Alder reaction (HDA). In this work, computational calculation of HDA between natural quinonemethides (tingenone and isopristimerol) and hypothetical orthoquinones has been performed at the M06-2X/6-31G(d) level of theory. We have located all the HDA transition states supporting the biogenetic route via HDA cycloadditions. We found that all reactions take place through a concerted inverse electron demand and asynchronous mechanism. The enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.

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

Theoretical study of the Diels-Alder reaction between o-benzoquinone and norbornadiene

The reaction between norbornadiene and o-benzoquinone is an important step in polyalicyclic rigid structures synthesis. It has been considered that this reaction is an example of Diels-Alder (DA) and hetero-Diels-Alder (HDA) cycloadditions with o-benzoquinone acting as diene (forming C-C bonds) and heterodiene (forming O-C bonds). We have performed a Density Functional Theory study of this reaction, employing B3LYP, mPW1PW91, and B1B95 functionals and 6-31G(d,p) and 6-31+G(d,p) Gaussian type basis sets. The results indicate that Diels-Alder is a feasible mechanism for both reactions, but should not be the main route to the formation of products with C-C bonds.

Biosynthesis of Grandione: An Example of Tandem Hetero Diels-Alder/Retro-Claisen Rearrangement Reaction?

Mechanistic theoretical studies about the feasibility of the traditional proposed mechanism of formation for icetexane diterpene dimer grandione were assessed using density functional method at the M06-2X/6-31G(d,p) level of theory. Bulk water solvent effects were taken into account implicitly using the polarizable continuum model (SCI-PCM). The results were compared with the selectivity found in the biomimetic synthesis performed by experimental research groups. The relative free energy calculation shows that the one-step H-DA formation mechanism nominated in the literature is not a viable mechanism. We found that an alternative competing Tandem pathway is consistent with the experimental trends. Thus, our results suggested that the compound grandione is formed via a H-DA/retro-Claisen rearrangement and not by the traditional H-DA mechanism proposed early in the experimental studies. The H-DA initial step produce a biecyclic adduct followed by a domino retro-Claisen rearrangement that releases the energy strain of the bicyclic intermediary. Steric issues and hyperconjugation interactions are the mainly factors driving the reaction nature and the selectivity in the formation reaction. Finally, the enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.

Chrysophanol anthrone: a theoretical study on the potential energy surface

Abstract The potential energy surface (PES) of chrysophanol anthrone, the active component of Goa Powder, was systematically explored and thoroughly scrutinised via density functional theory, in order to gain an understanding of its physicochemical properties. In particular, we focused on the rotations of the two hydroxyl-phenyl dihedral angles. A picture with a four stable rotamers emerged where only the most stable conformer has a planar structure and the less stable conformer has the maximum deviation from planarity. The computed PES shows that the energy barriers for the conformer interconversion are less than 15 kcal/mol. From the analysis of the calculated intramolecular hydrogen bond enthalpy, we conclude that the number of the intramolecular hydrogen bonds governs the conformer stability. Additionally, the conformational equilibrium was pursued by means of an analysis of the energy of OH internal rotation barriers. The total energy changes were decomposed in an electrostatic decomposition scheme in order to gain an insight into the effects governing the torsional barrier and preferred conformations. This analysis shows that the interplay between the repulsive and attractive potentials causes the conformer stability, where the attractive term dominates the conformer stabilisation.