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Drug metabolism of thiophene containing substrates by cytochrome P450s (CYP450) leads to toxic side effects, for example, nephrotoxicity (suprofen, ticlopidine), hepatotoxicity (tienilic acid), thrombotic thrombocytopenic purpura (clopidogrel), and aplastic anemia (ticlopidine). The origin of toxicity in these cases has been attributed to two different CYP450 mediated metabolic reactions: S-oxidation and epoxidation. In this work, the molecular level details of the bioinorganic chemistry associated with the generation of these competitive reactions are reported. Density functional theory was utilized (i) to explore the molecular mechanism for S-oxidation and epoxidation using the radical cationic center Cpd I [(iron(IV)-oxo-heme porphine system with SH(-) as the axial ligand, to mimic CYP450s] as the model oxidant, (ii) to establish the 3D structures of the reactants, transition states, and products on both the metabolic pathways, and (iii) to examine the potential energy (PE) profile for both the pathways to determine the energetically preferred toxic metabolite formation. The energy barrier required for S-oxidation was observed to be 14.75 kcal/mol as compared to that of the epoxidation reaction (13.23 kcal/mol) on the doublet PE surface of Cpd I. The formation of the epoxide metabolite was found to be highly exothermic (-23.24 kcal/mol), as compared to S-oxidation (-8.08 kcal/mol). Hence, on a relative scale the epoxidation process was observed to be thermodynamically and kinetically more favorable. The energy profiles associated with the reactions of the S-oxide and epoxide toxic metabolites were also explored. This study helps in understanding the CYP450-catalyzed toxic reactions of drugs containing the thiophene ring at the atomic level.

Phase-transfer catalysts (PTCs), currently, are one of the most important tools of chemists for performing organic reactions. PTCs accelerate several types of reactions in biphasic systems, giving excellent yields of the desired product. Most of the PTCs belong to the general formula NRX. In the recent past, several compounds possessing a novel scaffold with the general formula NLX have been reported as PTCs. In the NL species, a nitrogen atom with a formal positive charge accepts electron density from electron-donating ligands. Electronic structure studies reported in the literature confirmed the possibility of L → N coordination (donor-acceptor) interactions in these species, and thus, this class of compounds are known as divalent N compounds. These species are reported to exhibit better catalytic potential in comparison to the traditional NR systems. Some of the NL systems are found to be useful in asymmetric phase-transfer catalysis. Thus, these systems offer extensive opportunities for exploring the catalytic properties and novel mechanistic aspects associated with their unique electronic structure. In this paper, the synthesis, electronic, and structural properties and the applications in catalysis of the NL-based PTCs are reviewed with their bright future scope in catalytic organic chemistry.

A new simple and efficient method for the synthesis of 2-phenylnaphthalenes from electron-rich 1-styryl-2-methoxybenzenes has been described. The reaction proceeds via TFA catalyzed C-C bond cleavage followed by intermolecular [4+2]-Diels-Alder cycloaddition of an in situ formed styrenyl trifluoroacetate intermediate. The quantum chemical calculations identified the transition state for the cycloaddition reaction and helped in tracing the reaction mechanism. The method has been efficiently utilized for synthesis of the phenanthrene skeleton and a naphthalene-based potent and selective ER-β agonist.

Azines (2,3-diaza-1,3-butadienes): structure, electronic structure, tautomerism, and their applications in organic synthesis, medicinal chemistry and materials chemistry.

Drugs carrying an unsaturated C═C center (such as furans) form reactive epoxide metabolites and cause irreversible mechanism-based inactivation (MBI) of cytochrome P450 (CYP450) activity, through covalent modification of amino acid residues. Though this reaction is confirmed to take place in the active site of CYPs, the details of the reactions of furan (epoxidation and epoxide ring opening), the conditions under which MBI may occur, the residues involved, the importance of the heme center, etc. have yet to be explored. A density functional theory (DFT) study was carried out (i) to elucidate the reaction pathways for the generation of furan epoxide metabolite from furan ring by the model oxidant Cpd I (iron(IV)-oxo heme-porphine radical cation, to mimic the catalytic domain of CYPs) and (ii) to explore different reactions of the furan epoxide metabolite. The energy profiles of the competitive pathways and the conditions facilitating MBI of CYPs by the reactive epoxide metabolite are reported. The rate-determining step for the overall metabolic pathway leading to MBI was observed to be the initial epoxidation, requiring ∼12 kcal/mol under the enzymatic conditions. The covalent adducts (inactivator complexes) are highly stable (∼-46 to -70 kcal/mol) and may be formed due to the reaction between furan epoxide and nucleophilic amino acid residues such as serine/threonine, preferably after initial activation by basic amino acids.

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The present study aims to investigate the molecular basis of water sorption behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL). It was hypothesized, that the amount of water sorbed by a crystalline solid is governed by the surface molecular environment of different crystal facets and their relative abundance to crystal surface. Water sorption behavior was measured using a dynamic vapor sorption analyzer. The surface molecular environment of different crystal facets and their relative contribution were determined using single crystal structure evaluation and face indexation analysis, respectively. The surface area-normalized water sorption for rivaroxaban (RIV), malonic acid (MAL), and RIV-MAL at 90% RH/25 °C was 0.28, 92.6, and 11.1% w/w, respectively. The crystal surface of MAL had a larger contribution (58.7%) of hydrophilic (Hphi) functional groups and showed the “highest” water sorption (92.6% w/w). On the contrary, RIV had a larger surface contribution (65.2%) of hydrophobic (Hpho) functional groups, and the smaller contribution (34.8%) of Hphi+Hpho groups exhibited the “lowest” water sorption (0.28% w/w). The “intermediate” water sorption (11.1% w/w) by RIV-MAL, as compared to RIV, was ascribed to the increased surface contribution of Hphi+Hpho groups (from 34.8 to 42.1%) and reduced hydrophobic surface contribution (from 65.2 to 57.9%). However, the significantly higher water gained (∼39-fold) by the cocrystal as compared to RIV, despite the nominal change in the surface contributions, was further attributed to the relatively stronger hydrogen bonding interactions between the surface-exposed carboxyl groups and water molecules. The study highlights that the amount of water sorbed by the cocrystal is governed by the surface molecular environment and additionally by the strength of hydrogen bonding. This investigation has implications on designing materials with a desired moisture-sorption property.