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Nitreones are compounds with oxidation state 1 at the nitrogen, these compounds carry formal positive charge as well as two lone pairs of electrons at nitrogen center. These compounds are also known as divalent NI compounds and can be represented with the general formula L → N+ ← L, where L is an electron donating ligand. In the recent past, several divalent NI compounds have been reported with L = N-heterocyclic carbene (NHC), remote N-heterocyclic carbene (rNHC), carbocyclic carbene (CCC) and diaminocarbene. Recently, our group reported that a novel six-membered CCC (cyclohexa-2,5-diene-4-[diaminomethynyl]-1-ylidene) can stabilize N+ center in nitreones. As an independent carbene, this species is very unstable. In this work, modulation of this CCC using (a) annulation, (b) heterocyclic ring modification, (c) substitutions adjacent to the carbenic carbon, (d) exocyclic double bond insertion and (e) ring contraction, has been reported. These modulations and quantum chemical analyses helped in the identification of five new six-membered CCCs which carry improved donation and stability properties. Further, these CCCs were employed in the design of new divalent NI compounds (nitreones) which carry coordination bonds between ligands and N+ center. The molecular and electronic structure properties, and the donor→acceptor coordination interactions present in the resultant low oxidation state divalent NI compounds have been explored.

Cognitive decline is one of the serious complications associated with diabetes mellitus (T2DM) of type-2. In this reported work, the effect of aqueous sukkari dates seed extract (ASSE) was evaluated in T2DM-induced rats. T2DM was induced using intraperitoneal injection of nicotinamide and streptozocin (STZ) administration. The diabetic rats were then treated orally with 200 mg/kg and 400 mg/kg of dates seed extract for 30 days and results were compared with metformin-treated groups. The memory functions were assessed using three maze models. Glucose and insulin levels in the blood and acetylcholine, acetylcholinesterase brain homogenates were estimated. The results showed a significant reduction in transfer latency (TL) (

Diabetes is a metabolic disorder prevalent across the globe and is known to cause brain dysfunction, especially memory and cognitive decline. The current study investigates the effect of aqueous Ajwa seeds extract (AASE) on type-2 diabetes mellitus (T2DM)-induced memory deficits using a rat model. T2DM was induced by an administration of nicotinamide (120 mg/kg, i.p.) and streptozotocin (STZ) (60 mg/kg, i.p.). AASE (200 and 400 mg/kg, p.o.) were treated to T2DM rats for 30 days and the results were compared with the metformin (200 mg/kg). Elevated plus maze (EPM), Y-maze, and novel object recognition (NOR) tests were performed to assess the memory functions. The blood glucose and plasma insulin levels were estimated to assess the anti-diabetic effects of AASE. Acetylcholine (ACh) and acetylcholinesterase (AChE) levels were estimated from brain homogenates to assess cholinergic transmission. Treatment with AASE resulted in the reversal of behavioral deficits. EPM showed, a significant reduction in transfer latency (TL) among T2DM rats. High exploration time with a novel object and improvement in discrimination index were observed among treated groups during the NOR test. The Y-Maze test improved the entries and also time spent in the novel arm. Moreover, treatment of AASE reversed hyperglycemic and enhanced plasma insulin levels (200 mg/kg: 3.81 ± 0.08 ng/ml and 400 mg/kg: 4.09 ± 0.10 ng/ml) among T2DM rats (2.81 ± 0.15 ng/ml). Improved ACh levels (200 mg/kg: 186.6 ± 9.51 pg/mg protein and 400 mg/kg: 165.5 ± 9.25 pg/mg protein) and reduced AChE levels (200 mg/kg: 0.29 ± 0.02 ng/mg protein and 400 mg/kg: 0.32 ± 0.03 ng/mg protein) were also noted in the brain of AASE treated groups as referred to diabetic group (ACh: 107.1 ± 7.16 pg/mg protein and AChE: 0.51 ± 0.03 ng/mg protein). The above results were found to be comparable with the metformin-treated groups. From the results, it can be concluded that AASE has the potential to improve T2DM associated cognitive deficits.

Nitreones are compounds with oxidation state 1 at the nitrogen, these compounds carry formal positive charge as well as two lone pairs of electrons at nitrogen center. These compounds are also known as divalent N

Remote N-heterocyclic carbenes (rNHCs), such as N-methyl-4-pyridylidene, are known to form coordination complexes with TMs. Herein, it is established that rNHCs can also coordinate to the N+ centre. Synthesis of some novel divalent NI complexes with the general formula (rNHC)→N+ ←(NHC) and (rNHC)→N+ ←(rNHC) was achieved, and X-ray diffraction studies supported the coordination bond character between the rNHCs and the N+ centre. Quantum chemical analysis established the presence of divalent NI character at the central nitrogen in these systems.

Guanylthiourea (GTU) derivatives were identified as possible anti-malarial agents, recently, using in vitro studies on Plasmodium falciparum. This article gives an account of the in vivo anti-malarial activity of GTU derivatives against experimental rodent malaria. A total of 20 synthesized GTU derivatives were evaluated for in vivo antimalarial activity, out of which six showed encouraging results; one compound appeared to have curative potential. Molecular docking and molecular dynamics analysis were carried out to understand the molecular level interactions.

Dihydropyridine derivatives 1–31 were synthesized via one-pot solvent free condition and screened for in vitro against α-amylase and α-glucosidase enzyme. The synthetic derivatives 1–31 showed good α-amylase inhibition in the range of IC50 = 2.21 ± 0.06–9.97 ± 0.08 µM, as compared to the standard drug acarbose (IC50 = 2.01 ± 0.1 µM) and α-glucosidase inhibition in the range of IC50 = 2.31 ± 0.09–9.9 ± 0.1 µM as compared to standard acarbose (IC50 = 2.07 ± 0.1 µM), respectively. To determine the mode of binding interactions of synthetic molecules with active sites of enzyme, molecular docking studies were also performed. Different spectroscopic techniques such as 1H, 13C NMR, EI-MS, and HREI-MS were used to characterize all the synthetic compounds.

Carbocyclic carbenes (CCCs) are a class of nucleophilic carbenes which are very similar to N-heterocyclic carbenes (NHCs) in terms of their reactivity, but they do not contain a stabilizing heteroatom in their cyclic ring system. In this study, 17 representative known CCCs and 34 newly designed CCCs are evaluated using quantum chemical methods, and the results are compared in terms of their stability, nucleophilicity, and proton affinity (PA) parameters. The results are divided on the basis of ring size of the known and reported CCCs. The stability, nucleophilicity, PA, complexation energy, and bond strength-related parameters were estimated using M06/6-311++G(d,p) method. The results indicated that the CCCs known in the literature are strong σ-electron donating species and have considerable π-accepting properties. This study led to the design and identification of a few new CCCs with dimethylamine and diaminomethynyl substituents which can be singlet stable and are substantially nucleophilic. © 2018 Wiley Periodicals, Inc.

Coordination chemistry of bonds between main group elements and electron donating ligands as in L →E (where E is electron acceptor centre like C0, Si0, N1, P1, As1, B1 and L is an electron donating N-heterocyclic carbene) has been recently gaining attention. Many important drugs have nitrogen atom as an electron acceptor center and can be represented by two general formulae: (L →N←L)⊕ and L →N-R. Divalent N1 compounds possess two lone pairs at central nitrogen and low nucleophilicity associated with them is found to be of importance. In this article, electronic structure analysis of drug molecules like picloxydine, chlorhexidine, and moroxydine was performed at B3LYP/6-311 ++G(d,p) level of theory. Evaluation of electron localization function (ELF), molecular orbitals, charge density, nucleophilicity, proton affinity and complexation energy estimation confirms the presence of coordination bonds (L →N←L)⊕ in the above mentioned drug molecules in their cationic state. Further, electronic structure analysis of drugs like clonidine, apraclonidine, brimonidine and xylazine indicated the presence of electronic structure similar to L →N-R systems.

In this work, iminothiazolidin-4-one derivatives were explored as selective GSK-3β inhibitors. Molecular docking analysis was carried to design a series of compounds, which were synthesized using substituted thiourea, 2-bromoacetophenones and benzaldehydes. Out of the twenty five compounds synthesized during this work, the in vitro evaluation against GSK-3 led to the identification of nine compounds with activity in lower nano-molar range (2-85 nM). Further, in vitro evaluation against CDK-2 showed five compounds to be selective towards GSK-3.

Remote N-heterocyclic carbenes (rNHCs), such as N-methyl-4-pyridylidene, are known to form coordination complexes with TMs. Herein, it is established that rNHCs can also coordinate to the N

The dative-bond representation (L→E) in compounds with main group elements (E) has triggered extensive debate in the recent past. The scope and limits of this nonclassical coordination bond warrant comprehensive exploration. Particularly compounds with (L→N←L')(+) arrangement are of special interest because of their therapeutic importance. This work reports the design and synthesis of novel chemical species with the general structural formula (L→N←L')(+) carrying the unusual ligand cyclohexa-2,5-diene-4-(diaminomethynyl)-1-ylidene. Four species belonging to the (L→N←L')(+) class carrying this unconventional ligand were synthesized. Quantum chemical and X-ray diffraction analyses showed that the electronic and geometric parameters are consistent with those of already reported divalent N(I) compounds. The molecular orbital analysis, geometric parameters, and spectral data clearly support the L→N and N←L' interactions in these species. The newly identified ligand has the properties of a reactive carbene and high nucleophilicity.

The Paal–Knorr synthesis of furan, pyrrole and thiophene rings is one of the most important methods of generating these very important heterocycles, but the mechanism of this reaction is not well understood. Though several mechanistic paths are suggested, the exact energy requirements of this reaction, the structural features of transition states associated with the cyclization step, have not been established, especially for furan and thiophene synthesis. In this work, we explore the mechanism of the Paal–Knorr method and establish the energy requirements, using quantum chemical methods. The Paal–Knorr reaction to give furans is endergonic by 3.7 kcal mol−1 whereas the same reaction is exergonic for pyrrole and thiophene generation by 16.4 and 15.9 kcal mol−1, using G2MP2 method. The cyclization step is associated with high energy barrier, however, explicit water participation reduces the barrier significantly. For example, under the neutral condition two water mediated pathways – (i) monoenol and (ii) hemiketal, are possible on the reaction leading to furan. The cyclization step in these two pathways require 28.9 and 27.1 kcal mol−1, respectively. The ring formation step becomes highly favorable in the presence of H3O+ with a barrier of only 11.5 kcal mol−1 (solvent phase) from the monoenol to dihydrofuran derivative and 5.5 kcal mol−1 (solvent phase) from hemiketal to dihydroxy dihydrofuran derivative. Similarly, a water mediated pathway involving the intermediacy of hemialcohols has been found to be energetically preferred mechanism for pyrrole and thiophene also.

Guanylthiourea (GTU) has been identified as an important antifolate antimalarial pharmacophore unit, whereas, 4-amino quinolones are already known for antimalarial activity. In the present work molecules carrying 4-aminoquinoline and GTU moiety have been designed using molecular docking analysis with PfDHFR enzyme and heme unit. The docking results indicated that the necessary interactions (Asp54 and Ile14) and docking score (−9.63 to −7.36 kcal/mmol) were comparable to WR99210 (−9.89 kcal/mol). From these results nine molecules were selected for synthesis. In vitro analysis of these synthesized compounds reveal that out of the nine molecules, eight show antimalarial activity in the range of 0.61–7.55 μM for PfD6 strain and 0.43–8.04 μM for PfW2 strain. Further, molecular dynamics simulations were performed on the most active molecule to establish comparative binding interactions of these compounds and reference ligand with Plasmodium falciparum dihydrofolate reductase (PfDHFR).

An efficient, metal and base-free, chemoselective synthesis of aryl-, heteroaryl-, and alkyl primary amines from the corresponding boronic acids has been achieved at ambient temperature mediated by [bis(trifluoroacetoxy)iodo]benzene (PIFA) and N-bromosuccinimide (NBS) using cyanamidyl/arylcyanamidyl radicals as the aminating species. The primary amine compounds were initially obtained as their corresponding ammonium trifluoroacetate salts which, on treatment with aq NaOH, provide the free amines. Finally, the primary amines were isolated through column chromatography over silica-gel using hexane-EtOAc solvent system as the eluent. The reactions are sufficiently fast, completing within 1 h. Quantum chemical calculations in combination with experimental observations validate that the ipso amination of substituted boronic acids involves the formation of cyanamidyl/arylcyanamidyl radical, followed by regiospecific interaction of its nitrile-N center with boron atom of the boronic acids, leading to chemoselect...

An efficient, metal and base-free, chemoselective synthesis of aryl-, heteroaryl-, and alkyl primary amines from the corresponding boronic acids has been achieved at ambient temperature mediated by [bis(trifluoroacetoxy)iodo]benzene (PIFA) and N-bromosuccinimide (NBS) using cyanamidyl/arylcyanamidyl radicals as the aminating species. The primary amine compounds were initially obtained as their corresponding ammonium trifluoroacetate salts which, on treatment with aq NaOH, provide the free amines. Finally, the primary amines were isolated through column chromatography over silica-gel using hexane-EtOAc solvent system as the eluent. The reactions are sufficiently fast, completing within 1 h. Quantum chemical calculations in combination with experimental observations validate that the ipso amination of substituted boronic acids involves the formation of cyanamidyl/arylcyanamidyl radical, followed by regiospecific interaction of its nitrile-N center with boron atom of the boronic acids, leading to chemoselective primary amination.

Glycogen synthase kinase-3 is a constitutively acting, multifunctional serine threonine kinase, the role of which has been implicated in several physiological pathways and has emerged as a promising target for the treatment of type-II diabetes and Alzheimer’s disease. In order to provide a detailed understanding of the origin of selectivity determinants of ATP competitive inhibitors, molecular dynamics simulations in combination with MM-PBSA binding energy calculations were performed using crystal structures of GSK-3β and CDK-2 in complex with 12 ATP competitive inhibitors. Analysis of energy contributions indicate that electrostatic interaction energy dictates the selectivity of ATP competitive inhibitors against CDK-2. Key interactions as well as residues that potentially make a major contribution to the binding free energy were identified at the ATP binding site. This analysis stresses the need for the inhibitors to interact with Lys85, Thr138, and Arg141 in the binding site of GSK-3β to show selectivity. The residue-wise energy decomposition analysis further suggested the additional role of Gln185 in determining the selectivity of maleimides. The results obtained in this study can be utilized to design new selective GSK-3 ATP competitive inhibitors.

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.

A new class of compounds based on S-benzylated guanylthiourea has been designed as potential PfDHFR inhibitors using computer aided methods (molecular electrostatic potential, molecular docking). Several compounds in this class have been synthesized starting from guanylthiourea and alkyl bromides. In vitro studies showed that two compounds from this class are active with the IC50 value of 100 μM and 400 nM.

Glycogen Synthase Kinase-3 (GSK-3) is a constitutively acting multifunctional serine/threonine kinase, a role of which has been marked in several physiological pathways, making it a potential target for the treatment of many diseases, including Type-II diabe- tes and Alzheimer's. Design of GSK-3� selective inhibitor was the key challenge which led to the use of rational approaches like struc- ture based methods (molecular docking), and ligand based methods (QSAR, pharmacophore mapping) studies. These methods provide insights into the enzyme-ligand interactions and structure activity relationship of different sets of compounds for the design of promising GSK-3 inhibitors. Molecular dynamic simulation studies have additionally been performed to address key issues like the unique require- ment of prime phosphorylation of its substrate at P+4 by GSK-3� . An allosteric site has also been reported, where the binding of the pep- tide leads to the stabilization of the activation loop, resulting in the enhancement of the catalysis of enzymes. These studies are becoming useful in the design of therapeutically active discriminatory GSK-3 inhibitors. In this article, we present a review of recent efforts and fu- ture opportunities for the design of selective GSK-3� inhibitors.