Potential energy surface of thionylimide

The potential energy surface (PES) of thionylimide has been searched using ab initio MO and density functional calculations. The electronic structures of the isomers of HNSO have been studied using the HF/6‐31+G*, MP2(full)/6‐31+G*, and B3LYP/6‐31+G* levels. Final energies of these molecules have been calculated at the high‐accuracy G2 and CBS‐Q levels. The probable pathways of isomerization of thionylimide to its isomers (e.g., thiocyanic acid, HONS, nitrosothiols) have been explored by studying the three‐ or four‐membered transition states. This study identified total eight possible isomers ( 1–8 ) of HNSO, of which four ( 1–4 ) have already been realized experimentally. Of the remaining four ( 5–8 ), at least two ( 5, 7 ) can be generated experimentally. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006     

Keto<==>enol, imine<==>enamine, and nitro<==>aci-nitro tautomerism and their interrelationship in substituted nitroethylenes. Keto, imine, nitro, and vinyl substituent effects and the importance of H-bonding

Tautomeric isomers and conformers of 2-nitrovinyl alcohol (1), 2-nitrovinylamine (2), and 1-nitro-propene (3) are reported at the MP2 and B3LYP levels of theory, using the 6-31G* basis set, with energy evaluation at B3LYP/6-311+G** and G2MP2. The nitroalkenes are the global minima on their respective potential energy surfaces. The barriers for the concerted 1,5-H transfer to the corresponding nitronic acids amount to only 5.0 kcal/mol for 1, 13.2 kcal/mol for 2, and a sizable 37.8 kcal/mol for 3. Whereas the aci-nitro tautomer of 2-nitrovinyl alcohol is easily accessible, beta-iminonitronic acid has little kinetic stability. H-bonding is a strong stabilizing factor in these nitroalkenes, estimated at 7.0 and 3.7 kcal/mol for the OH and NH2 derivatives, respectively, while its stabilization in their nitronic acids amounts to as much as 13 kcal/mol. The H-bonds are evident from the very short O...H and N...H distances and are characterized by bond critical points. The NO2 substituent effect of about 11.4 kcal/mol at G2MP2 on both the classical keto <==> enol and imine <==> enamine tautomeric processes stabilizes the nitroethylene derivatives. The keto, imine, and vinyl substituent effects at G2MP2 on the nitro <==> aci-nitro tautomeric process are also determined as are their pi-resonance components. The substituents have a large influence on the ionization energies of the nitroethylene derivatives.     

Identification of Druggable Targets for Acinetobacter baumannii Via Subtractive Genomics and Plausible Inhibitors for MurA and MurB

Emergence of the multidrug-resistant pathogens has rendered the current therapies ineffective thereby, resulting in the need for new drugs and drug targets. The accumulating protein sequence data has initiated a drift from classical drug discovery protocols to structure-based drug designing. In the present study, in silico subtractive genomics approach was implemented to find a set of potential drug targets present in an opportunist bacterial pathogen, Acinetobacter baumannii (A. baumannii). Out of the 43 targets identified, further studies for protein model building and lead-inhibitor identification were carried out on two cell-essential targets, MurA and MurB enzymes (of A. baumannii designated as MurA_Ab and MurB_Ab) involved in the peptidoglycan biosynthesis pathway of bacteria. The homology model built for each of them was further refined and validated using various available programs like PROCHECK, Errat, ProSA energy plots, etc. Compounds showing activity against MurA and MurB enzymes of other organisms were collected from the literature and were docked into the active site of MurA_Ab and MurB_Ab enzymes. Three inhibitors namely, T6361, carbidopa, and aesculin, showed maximum Glide score, hydrogen bonding interactions with the key amino acid residues of both the enzymes and acceptable ADME properties. Furthermore, molecular dynamics simulation studies on MurA_Ab–T6361 and MurB_Ab–T6361 complexes suggested that the ligand has a high binding affinity with both the enzymes and the hydrogen bonding with the key residues were stable in the dynamic condition also. Therefore, these ligands have been propsed as dual inhibitors and promising lead compounds for the drug design against MurA_Ab and MurB_Ab enzymes.     

Importance of cytochromes in cyclization reactions: Quantum chemical study on a model reaction of proguanil to cycloguanil

Proguanil, an anti‐malarial prodrug, undergoes cytochrome P450 catalyzed biotransformation to the pharmacologically active triazine metabolite (cycloguanil), which inhibits plasmodial dihydrofolate reductase. This cyclization is catalyzed by CYP2C19 and many anti‐malarial lead compounds are being designed and synthesized to exploit this pathway. Quantum chemical calculations were performed using the model species (Cpd I for active species of cytochrome and N4‐isopropyl‐N6‐methylbiguanide for proguanil) to elucidate the mechanism of the cyclization pathway. The overall reaction involves the loss of a water molecule, and is exothermic by approximately 55 kcal/mol, and involves a barrier of approximately 17 kcal/mol. The plausible reaction pathway involves the initial H‐radical abstraction from the isopropyl group by Cpd I, followed by two alternative paths‐ (i) oxygen rebound to provide hydroxyl derivative and (ii) loss of additional H‐radical to yield 1,3,5‐triazatriene, which undergoes cyclization. This study helped in understanding the role of the active species of cytochromes in this important cyclization reaction. © 2014 Wiley Periodicals, Inc.     

Formation of Periodic γ‐Turns in α/β‐Hybrid Peptides: DFT and NMR Experimental Evidence

Hybrid peptidic oligomers comprising natural and unnatural amino acid residues that can exhibit biomolecular folding and hydrogen‐bonding mimicry have attracted considerable interest in recent years. While a variety of hybrid peptidic helices have been reported in the literature, other secondary structural patterns such as γ‐turns and ribbons have not been well explored so far. The present work reports the design of novel periodic γ‐turns in the oligomers of 1:1 natural‐α/unnatural trans‐β‐norborenene (TNAA) amino acid residues. Through DFT, NMR, and MD studies, it is convincingly shown that, in the mixed conformational pool, the heterogeneous backbone of the hybrid peptides preferentially adopt periodic 8‐membered (pseudo γ‐turn)/7‐membered (inverse γ‐turn) hydrogen bonds in both polar and non‐polar solvent media. It is observed that the stereochemistry and local conformational preference of the β‐amino acid building blocks have a profound influence on accessing the specific secondary fold. These findings may be of significant relevance for the development of molecular scaffolds that facilitate desired positioning of functional side‐chains.     

Metformin and glitazones: does similarity in biomolecular mechanism originate from tautomerism in these drugs?

This theoretical study attempts to find out similarity between metformin and glitazone class of antidiabetic drugs. It was found that some tautomeric forms of both metformin and thiazolidinedione ring of glitazones have similar molecular electrostatic potential (MESP) surface and may bind to a common complementary surface. Complexation and docking studies were also carried out in order to support this hypothesis. Copyright © 2007 John Wiley & Sons, Ltd.     

Ti(III)-mediated opening of 2,3-epoxy alcohols to build five-membered carbocycles with multiple chiral centres

Stereoselective construction of highly substituted five-membered carbocycles with multiple chiral centres is described. Sharpless kinetic resolution was applied as the key step to prepare the required 2,3-epoxy alcohols and a Ti(III) radical mediated opening of the epoxide ring followed by intramolecular trapping of the generated radical with a suitably placed α,β-unsaturated ester resulted in the formation of five-membered carbocycles with up to three consecutive new chiral centres stereoselectively fixed.     

Theoretical studies on the conformations of selenamides

Ab initio HF/6-31+G*, MP2/6-31+G*, B3LYP/6-31+G* level calculations have been performed on HSe-NH₂ to estimate the Se-N rotational barriers and N-inversion barriers. Two conformers have been found withsyn andanti arrangement of the NH₂ hydrogens with respect to Se-H bond. The N inversion barriers in selenamide are 1.65, 2.47, 1.93 kcal/mol and the Se-N rotational barriers are 6.58, 6.56 and 6.12 kcal/mol respectively at HF/6-31+G*, MP2/6-31+G* and B3LYP/6-31+G* levels respectively. The n_N →Σ *_Se-H negative hyperconjugation is found to be responsible for the higher rotational barriers.     

A novel acid-catalyzed C5-alkylation of oxindoles using alcohols

A novel C5-alkylation of oxindoles using alcohols as alkylating agents under acid catalysis is described for the first time. The reactions of various benzylic, allylic and propargylic alcohols are studied to obtain the corresponding 5-substituted oxindoles in good yields.