Synthesis,spectral characterization,and biological evaluation of imidazole‐substituted pyridine‐2‐amine and benzo‐substituted imidazole‐2‐amine

A series of new imidazole‐substituted pyridine‐2‐amine and benzo‐substituted imidazol‐2‐amine 3 – 12 were synthesized by treating various amines 1(a – d) with alkyl/aryl isothiocyanate 2(a‐c) at 60–90°C in isopropyl alcohol without using any catalyst with high yields. The structures of all the newly synthesized compounds were characterized using IR, NMR (¹H, ¹³C), mass, and elemental analyses. All the newly synthesized compounds were screened for their in vitro antioxidant and antimicrobial activities to understand their biological potency. All the title compounds exhibited good antioxidant and antimicrobial activities in vitro when compared to the standard drugs.     

Diffusion Kinetics of Vitamin B12 from Alginate and Poly(vinyl acetate) Based Gel Scaffolds for Targeted Drug Delivery

Abstract

The research described here probed the thermodynamics and kinetics of Vitamin B₁₂ release from two types of polymeric gel scaffolds for targeted drug delivery applications. The polymeric gel scaffolds were successfully prepared from sodium alginate and polyvinyl acetate (PVA) using crosslinking and casting mechanisms, respectively. Vitamin B₁₂ was effectively blended into the polymeric gel scaffolds during their synthesis processes. The release of Vitamin B₁₂ from the polymeric gel scaffolds was characterized by immersing the scaffolds in a brine solution at various temperatures (25?°C, 32?°C and 37?°C) and, simultaneously, the transient concentrations were measured using a UV visible spectrophotometer. The sodium alginate gel scaffolds exhibited a more rapid release of Vitamin B₁₂ as compared to the PVA gel scaffolds. The Vitamin B₁₂ release kinetics from the alginate and PVA scaffolds were characterized by fitting the experimental data with various diffusion kinetic models. The Vitamin B₁₂ release from the alginate gel scaffolds followed the Peppas-Sahlin model, whereas releases from the PVA gel scaffolds were fitted to the Hopfenberg model. The diffusion coefficients for the alginate scaffolds with respect to the three temperatures were found to be 15.72?m²/s, 17.17?m²/s and 18.58?m²/s respectively whereas the diffusion coefficients for the PVA scaffolds with respect to the three temperatures were found to be 0.23?m²/s, 0.29?m²/s and 0.32?m²/s respectively. The activation energies (E_a) for the two types of polymeric scaffolds were calculated using the Stannett equation and found to be 10.38?kJ.mol^?1 and 20.47?kJ.mol^?1 for the alginate and PVA scaffolds, respectively, for all three temperatures.     

QSAR and Molecular Docking Studies of Pyrimidine-Coumarin-Triazole Conjugates as Prospective Anti-Breast Cancer Agents

Cancer is a life-threatening disease and is the second leading cause of death worldwide. Although many drugs are available for the treatment of cancer, survival outcomes are very low. Hence, rapid development of newer anticancer agents is a prime focus of the medicinal chemistry community. Since the recent past, computational methods have been extensively employed for accelerating the drug discovery process. In view of this, in the present study we performed 2D-QSAR (Quantitative Structure-Activity Relationship) analysis of a series of compounds reported with potential anticancer activity against breast cancer cell line MCF7 using QSARINS software. The best four models exhibited a r² value of 0.99. From the generated QSAR equations, a series of pyrimidine-coumarin-triazole conjugates were designed and their MCF7 cell inhibitory activities were predicted using the QSAR equations. Furthermore, molecular docking studies were carried out for the designed compounds using AutoDock Vina against dihydrofolate reductase (DHFR), colchicine and vinblastine binding sites of tubulin, the key enzyme targets in breast cancer. The most active compounds identified through these computational studies will be useful for synthesizing and testing them as prospective novel anti-breast cancer agents.     

Inner-sphere electron transfer in metal-cation chemistry

Bond activation of organic molecules by metal cations is usually rationalized either in terms of the chemistry of Lewis acids or via oxidative addition of metal fragments to R---X bonds, that is, R---X+M⁺→R---M⁺---X→products. In most of these mechanisms, the positive charge is assumed to be located on the metal center. Here, we propose an alternative mechanism, to which we refer as inner-sphere electron transfer (ET). Thus, provided that certain conditions are fulfilled, the insertion species R---M⁺---X may isomerize via ET to [ R⁺ MX] structures with the positive charge located mostly at the organic residue R. If R---M⁺---X and [ R⁺ MX] are not just resonance structures but distinct minima on the related potential-energy surfaces, there also exists a transition structure between the two, that is, an ET-TS. Here, the role of inner sphere ET in organometallic gas-phase reactions and the possible existence of ET-TSs are discussed for a series of examples investigated both computationally and experimentally.     

Thiacyclobutadiene and thiabenzene: A comparative theoretical analysis

The two title compounds have been investigated theoretically using an ab initio SCF-MO treatment at the minimal STO-3G level. It has been found that in the most stable conformation thiacyclobutadiene has all atoms approximately in the same plane except for the H atom bonded to sulphur (i.e. a pyramidal sulphur). On the other hand, in the most stable conformation of thiabenzene, the sulphur atom not only is pyramidal, but also ~10° out of the plane containing the carbon system. The barriers to pyramidal inversion at the sulphur centres are ~48 and ~56 $\text{kcal}\text{mol}$ for thiacyclobutadiene and thiabenzene, respectively. The properties of these molecules are rationalized by means of Perturbation Molecular Orbital (PMO) theory.     

Searching for the second oxidant in the catalytic cycle of cytochrome P450: a theoretical investigation of the iron(III)-hydroperoxo species and its epoxidation pathways

Iron(III)-hydroperoxo, [Por(CysS)Fe(III)-OOH](-), a key species in the catalytic cycle of cytochrome P450, was recently identified by EPR/ENDOR spectroscopies (Davydov, R.; Makris, T. M.; Kofman, V.; Werst, D. E.; Sligar, S. G.; Hoffman, B. M. J. Am. Chem. Soc. 2001, 123, 1403-1415). It constitutes the last station of the preparative steps of the enzyme before oxidation of an organic compound and is implicated as the second oxidant capable of olefin epoxidation (Vaz, A. D. N.; McGinnity, D. F.; Coon, M. J. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 3555-3560), in addition to the penultimate active species, Compound I (Groves, J. T.; Han, Y.-Z. In Cytochrome P450: Structure, Mechanism and Biochemistry, 2nd ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 1995; pp 3-48). In response, we present a density functional study of a model species and its ethylene epoxidation pathways. The study characterizes a variety of properties of iron(III)-hydroperoxo, such as the O-O bonding, the Fe-S bonding, Fe-O and Fe-S stretching frequencies, its electron attachment, and ionization energies. Wherever possible these properties are compared with those of Compound I. The proton affinities for protonation on the proximal and distal oxygen atoms of iron(III)-hydroperoxo, and the effect of the thiolate ligand thereof, are determined. In accordance with previous results (Harris, D. L.; Loew, G. H. J. Am. Chem. Soc. 1998, 120, 8941-8948), iron(III)-hydroperoxo is a strong base (as compared with water), and its distal protonation leads to a barrier-free formation of Compound I. The origins of this barrier-free process are discussed using a valence bond approach. It is shown that the presence of the thiolate is essential for this process, in line with the "push effect" deduced by experimentalists (Sono, M.; Roach, M. P.; Coulter, E. D.; Dawson, J. H. Chem. Rev. 1996, 96, 2841-2887). Finally, four epoxidation pathways of iron(III)-hydroxperoxo are located, in which the species transfers oxygen to ethylene either from the proximal or from the distal sites, in both concerted and stepwise manners. The barriers for the four mechanisms are 37-53 kcal/mol, in comparison with 14 kcal/mol for epoxidation by Compound I. It is therefore concluded that iron(III)-hydroperoxo, as such, cannot be a second oxidant, in line with its significant basicity and poor electron-accepting capability. Possible versions of a second oxidant are discussed.