Tautomerism in drugs with benzimidazole carbamate moiety: an electronic structure analysis

Several medicinally important compounds carry benzimidazole carbamate moiety. In the scientific literature, these molecules are represented in different tautomeric forms. In this report, conformational and tautomeric preferences were analyzed on the model benzimidazole carbamate (carbendazim), so as to understand the potential energy surface of the title compounds. Quantum chemical calculations have been performed using HF, B3LYP, and MP2 methods in gas phase and solvent phase on model benzimidazole carbamate to understand the conformational and tautomeric preferences. (1) PE surface of amide–imide tautomers, (2) electron distribution, (3) AIM analysis, (4) NBO charges, (5) 1,3-H shift, etc., have been investigated for carbendazim and its conformers. The molecular electrostatic potential (MESP) surfaces of carbendazim have been studied. Further to understand the polymorphism in benzimidazole carbamate, analysis of dimers of carbendazim has been carried out. The results indicate that a neglected tautomer is important and the tautomeric equilibrium is quite subtle in these systems and it should be extensively considered in all studies related to these drugs.     

Conformational polymorphism in bicalutamide: a quantum chemical study

Bicalutamide is an anti-neoplastic drug widely used for the treatment of prostate cancer and it exhibits conformational polymorphism. Three crystal structures of bicalutamide are reported as racemic mixtures, two of which are polymorphs. In addition, three co-crystals are also reported—two with organic coformers and one with adrenoreceptor (the macromolecular target). All the reported structures show significant conformational differences. Quantum chemical B3LYP/6-31+G(d,p) analysis has been carried out to understand the interplay of intra- and intermolecular interactions leading to the conformational preferences in this molecule. The difference between the two polymorphic forms has been traced to the C5–S8–C11–C12 torsional angle. Inside the cavity of androgen receptor, a completely different conformation is found but it does not correspond to any local minima on the potential energy surface of the drug. A relatively rigid torsional angle C11–C12–C15–N17 is also expected due to a strong five-membered ring intramolecular hydrogen bond (H–O13–C12–C15–O16), which has been reported to be desirable; quantum chemical analysis revealed that this rigidity is of the order of 11 kcal/mol. Ab initio calculations demonstrate that polymorphs and polymorphic co-crystals differ in the extent of intra- and intermolecular hydrogen bonding interactions. The strength of the intermolecular interactions associated with these structures is analyzed in terms of energy release due to dimerization.     

Computational study on the conformational preferences in nateglinide

Ab initio and semi‐empirical calculations were performed on the monomers, dimers and tetramers of the antidiabetic drug nateglinide to understand the conformational preferences and to explore their possible relation with polymorphism. The reported crystal structure of bis(nateglinide) hydronium chloride shows one asymmetric unit consisting of four different conformations of the drug nateglinide. The Becke, three‐parameter, Lee–Yang–Parr /6‐31+G(d,p) optimizations indicate that these conformers are energetically quite comparable and the differences disappear in gas phase. Our analysis shows that Φ (phi) torsion angle of this phenylalanine derivative is responsible for the observed differences in stability among the nateglinide conformations. Four different polymorphs of nateglinide (B, H, S and X2) were reported but the structural differences are not available. This quantum chemical study on the dimers of nateglinide helps in proposing the structures of polymorphs. As per the quantum chemical analysis, the dimer N‐44 is the structure of the stable polymorph, whereas, the dimers N‐AA, N‐CC and N‐AC are almost isoenergetic, thus proposed to be the structures of metastable state. The dimerization and tetramerization energies are estimated to be about ?9.0 and ?38.67 kcal/mol, respectively. The extra stability in tetrameric state compared with the dimeric form is attributed to additional hydrophobic and van der Waals interactions. Copyright © 2011 John Wiley & Sons, Ltd.     

A study on the BF3 directed lithiation of 3-chloro- and 3-bromopyridine

The BF₃-directed lithiation of 3-chloro- and 3-bromopyridine (1a and 1b, respectively) has been investigated. The reactions of 3-chloro- or 3-bromopyridine–BF₃ adduct with LDA (1.3/1.1 equiv) followed by quenching with benzaldehyde or iodine exclusively gave the C-2 substituted products. However, when 2.2 equiv of LDA and dimethyl disulfide was used, a C-6 substituted product was obtained. Dilithiation of 1a and 1b has been studied with and without the involvement of BF₃ complexation. The role of Li?F(BF₃) interactions has been investigated by experimental and DFT calculations.     

A new colorimetric chemodosimeter for Hg2+ based on charge-transfer compound of N-methylpyrrole with TCNQ

Reaction of N-methylpyrrole and 7,7,8,8-tetracyanoquinodimethane (TCNQ) furnishes an intense blue unsymmetrical charge-transfer compound through regioselective attachment of tricyanoquinodimethane at the 2-position of N-methylpyrrole which was found to be selective chemodosimeter for Hg²⁺ ions in CH₃CN:H₂O mixture (1:1 v/v, pH = 7.0, 0.01 M HEPES, 0.15 M NaCl) as well as in the solid state when supported on silica, over a variety of metal ions. A plausible mechanism for the sensing process has been proposed and supported through the characterization of the resulting Hg²⁺ complex and the density functional theory (DFT) studies.     

Thiazole–Chalcone Hybrids as Prospective Antitubercular and Antiproliferative Agents: Design,Synthesis, Biological,Molecular Docking Studies and In Silico ADME Evaluation

Compounds bearing thiazole and chalcone pharmacophores have been reported to possess excellent antitubercular and anticancer activities. In view of this, we designed, synthesized and characterized a novel series of thiazole–chalcone hybrids (1–20) and further evaluated them for antitubercular and antiproliferative activities by employing standard protocols. Among the twenty compounds, chalcones 12 and 7, containing 2,4-difluorophenyl and 2,4-dichlorophenyl groups, showed potential antitubercular activity higher than the standard pyrazinamide (MIC = 25.34 µM) with MICs of 2.43 and 4.41 µM, respectively. Chalcone 20 containing heteroaryl 2-thiazolyl moiety exhibited promising antiproliferative activity against the prostate cancer cell line (DU-145), higher than the standard methotrexate (IC₅₀ = 11 ± 1 µM) with an IC₅₀ value of 6.86 ± 1 µM. Furthermore, cytotoxicity studies of these compounds against normal human liver cell lines (L02) revealed that the target molecules were comparatively less selective against L02. Additional computational studies using AutoDock predicted the key binding interactions responsible for the activity and the SwissADME tool computed the in silico drug likeliness properties. The lead compounds generated through this study, create a way for the optimization and development of novel drugs against tuberculosis infections and prostate cancer.