Ab initio Computational Modeling of Glyphosate Analogs: Conformational Perspective

A historical perspective on the application of conformational analysis to structure-based ligand design approach is presented. The application of isodensity molecular electrostatic potential surfaces with the conformational energy surfaces (CES) have allowed us to reach pertinent conclusions for aiding synthetic and biochemical studies. Here we illustrate such an application on the modeling of the potent analogs of an important, environmentally stringent herbicidal compound glyphosate by constructing conformational energy surfaces. The systems were modeled by substituting F, Cl, and NH— OH moiety to the position of pharmacophoric nitrogen center in glyphosate structure. All the calculations were thoroughly performed with ab initio MO theory at Hartree–Fock method using 3-21G(d) basis functions. On the basis of the results, we identified the bioactive conformations for N-fluoro-glyphosate, N-chloro-glyphosate, and N-hydroxyamino-glyphosate as (−38^∘, 77^∘), (−61^∘, 111^∘), and (−167^∘, −169^∘), respectively. Geometry optimization of certain selected conformations of these compounds using hybrid DFT method with 6–31+G(d) basis functions provides nearly equal values of φ and ψ. Moreover, the results indicate that the global minimum structures of N-fluoro and N-chloro analogs of glyphosate show cyclic conformation whereas the N-hydroxyamino-glyphosate global minimum structure shows spyrocyclic and zig-zag conformation. Also, the predicted bioactive conformation of N-hydroxyamino analog optimally overlaps with glyphosate backbone in EPSPS complex with 0.1 Å RMSD value. However, the other two compounds slightly deviate from the backbone of glyphosate with RMSD of 0.92 Å for N-fluoro-glyphosate and 0.83 Å for N-chloro-glyphosate. The linear N-hydroxyamino-glyphosate exhibits relatively more number of intermolecular hydrogen bond interactions as compared to the other two analogs. Further, comparison of CES of previously studied glyphosate analogs such as N-hydroxy-glyphosate (2.2 μM) and N-amino-glyphosate (0.61 μM) with the present systems reveals the order of activity as: N-hydroxyamino-glyphosate > N-fluoro-glyphosate > N-chloro-glyphosate based on CES flexibility. Also, the calculated heats of formation of N-fluoro-glyphosate, N-chloro-glyphosate, and N-hydroxyamino-glyphosate are −288, −209, and −288 kcal/mol, respectively, which clearly indicate that the N-hydroxyamino and N-fluoro analogs of glyphosate are thermodynamically more stable than N-amino-glyphosate (−278 kcal/mol).     

Use of Molecular Electrostatic Potentials for Analysis of Anticonvulsant Activities of Phenylsuccinimides

Abstract

The present study was performed on a group of 27 derivatives of phenylsuccinimides, of which only 12 were active against maximal electrical shock in spite of the structural similarities of these compounds. The work consisted of four main parts: 1. crystallographic investigations of a subset of chosen compounds; 2. conformational analysis of characteristic molecules from the investigated series, performed by means of molecular mechanics calculations; 3. molecular orbital optimization of all the molecules using the MNDO method starting with conformations obtained in 2; 4. molecular electrostatic potential (MEP) analysis which was performed on the semiempirical (MNDO) and ab initio levels. This research showed that MEP maps provide a signature that distinguishes between active and inactive compounds. There are MEP minima close to the two carbonyl oxygens of the imide ring, and although the magnitude of the difference between the two minima is approximately constant, the sign of the difference provides an activity index. The initial orientations of phenylsuccinimide molecules in relation to the receptor are not equivalent and they depend on the potential distribution around both the succinimide molecules and around the receptor. In the active compounds the negative potential difference at the discussed points most probably influences the initial set-up of the molecules in relation to the receptor and results in a considerably higher probability of the molecules being bound at the right place on the receptor.     

Donor acceptor groups effect,polar protic solvents influence on electronic properties and reactivity of 2-Chloropyridine-4-carboxylic acid

The computational reckoning of 2-Chloropyridine-4-carboxylic acid (2CP4CA) was accomplished employing DFT/B3LYP with the root set as 6–311++G(d, p). The impact of polar protic solvents which are eco-friendly solvents (water, methanol, ethanol, 1-propanol) on 2CP4CA were analysed. To examine the solvent effect, vibrational investigations and NLO reports of 2CP4CA in dissimilar solvents were executed. Geometrical properties were also established in gas phase for 2CP4CA. Exercising VEDA program, the entire vibrational assignment was accomplished. Donor-acceptor exchanges were ascertained utilizing NBO scrutiny technique. Thermodynamic properties of 2CP4CA were analysed at different temperatures. By applying TD - DFT approach, theoretic UV–Vis absorption spectrum was procured in different solvents. In order to evaluate the complete electron concentration and sensitive spots of 2CP4CA, MEP coupled with FMO analyses were employed. HOMO along with LUMO orbitals and energy band gap were acquired for 2CP4CA employing dissimilar polar protic solvents. Additionally, ELF, LOL and charge transfer studies were also executed. RDG analysis has been exercised for revealing non-covalent interactions.     

Tuning of carbon bonds by substituent effects: an ab initio study

ABSTRACT

An ab initio study, at the MP2/aug-cc-pVTZ level of theory, is performed to study σ-hole bond in binary XH₃C···CNY complexes, where X = CN, F, NO₂, CCH and Y = H, OH, NH₂, CH₃, C₂H₅, Li. This type of interaction is labelled as ‘carbon bond’, since a covalently bonded carbon atom acts as the Lewis acid in these systems. The geometrical and energetic parameters of the resulting complexes are analysed in details. The interaction energies of these complexes are between ?4.97 kJ/mol in (HCC)H₃C···CNH and ?23.07 kJ/mol in (O₂N)H₃C···CNLi. It is found that the electrostatic interaction plays a key role in the overall stabilisation of these carbon-bonded complexes. To deepen the understanding of the nature of the carbon-bonding, the molecular electrostatic potential, natural bond orbital, quantum theory of atoms in molecules and non-covalent interaction index analyses are also used. Our results indicate that the carbon bond is favoured over the C-H···C hydrogen bond in the all complexes considered and may suggest the possible important roles of the C···C interactions in the crystal growth and design.     

Synthesis and anticonvulsant activity of new fluorinated N-phenyl- and N-benzyl-2-azaspiro[4.4]nonane- and [4.5]decane-1,3-dione derivatives: Part III

A series of N-phenyl- and N-benzyl-2-azaspiro[4.4]nonane- and [4.5]decane-1,3-diones containing a fluoro or trifluoromethyl substituents at the aryl ring was synthesized and tested for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous metrazole (sc.Met) tests. Among them, the most active were N-benzyl derivatives with fluoro and trifluoromethyl substituents especially at position-2 of the aryl moiety. The introduction of the phenyl ring at the imide nitrogen atom resulted in less active compounds. The results obtained showed that incorporation of fluoro or trifluoromethyl substituents increased the anticonvulsant activity in comparison to respective chloro, methoxy or methyl analogues. Crystallographically obtained conformation for one active and two inactive derivatives with trifluoromethyl substituents at position-2 or -3 of phenyl ring were initially used for molecular electrostatic potentials (MEP) calculation. The MEP distribution at carbonyl oxygen atoms was different for active and inactive molecules.