Sanjay K. Mandal

Cocrystals of telmisartan: characterization, structure elucidation, in vivo and toxicity studies

The present study reports novel cocrystals of telmisartan (TEL) with saccharin and glutaric acid. Crystal engineering approaches such as solution crystallization, solid-state grinding and slurry method have been utilized with the ultimate objective of improving the solubility of this BCS class II drug. The physical characterization revealed that the cocrystals are unique vis-a-vis thermal, spectroscopic and X-ray diffraction properties. Structural characterization showed that the cocrystals with saccharin and glutaric acid exist in monoclinic P21/c and triclinic P space groups, respectively. The improved solubility of telmisartan–saccharin (TEL–SAC) (nine-fold) and telmisartan–glutaric acid (two-fold) cocrystals in comparison with the free drug has been demonstrated in solubility experiments in phosphate buffer, pH 7.5. The TEL–SAC cocrystal remained stable in the aqueous medium for 6 hours as confirmed by PXRD. The AUC0–24 of TEL–SAC and TEL–GA was found to be 2-fold and 1.4-fold increased in terms of bioavailability than pure TEL, respectively. The in vivo antihypertensive activity of TEL–SAC in DOCA salt-induced hypertensive rats showed two-fold improved efficacy, while acute toxicity studies revealed no signs of toxicity in rats even at doses of 2000 mg kg−1 of body weight (BW). The new solid phase of telmisartan with saccharin represents a promising and viable opportunity for the manufacture of a drug product with improved therapeutic outcomes.

Hierarchical importance of coordination and hydrogen bonds in the formation of homochiral 2D coordination polymers and 2D supramolecular assemblies

In exploring the chemistry of reduced Schiff base derivatives of amino acids with Cu(II) ions, a series of homochiral two-dimensional (2D) coordination polymers (CPs) with a unique loop-like structure comprised of five Cu(II) centers, {[Cu2(Hsersal)2(H2O)]·2.5H2O}n, (1), {[Cu2(Hser-5OMe-sal)2(H2O)]·DMF}n (2), [Cu2(Hser-5NO2-sal)2(H2O)]n (3), {[Cu2(Hser-5Cl-sal)2(H2O)]·2H2O}n (4), {[Cu2(Hser-3Cl-sal)2(H2O)]·3H2O}n (5) and {[Cu2(Hser-o-Van)2(H2O)]·3H2O}n (6) [where H3sersal = N-(2-hydroxybenzyl)-serine, H3ser-5OMe-sal = N-(2-hydroxy-5-methoxybenzyl)-serine, H3ser-5NO2-sal = N-(2-hydroxy-5-nitrobenzyl)-serine, H3ser-5-Cl-sal = N-(2-hydroxy-5-chlorobenzyl)-serine, H3ser-3-Cl-sal = N-(2-hydroxy-3-chlorobenzyl)-serine, H3ser-o-van = N-(2-hydroxy-3-methoxybenzyl)-serine], have been isolated in good yields from the reaction of a methanolic solution of CuSO4·5H2O and potassium salt of the respective ligands (in a 1 : 1 ratio) either at room temperature or under reflux. In these CPs, the two Cu(II) centers have different coordination environments with one coordinated to a water molecule. Using a bifunctional linker, such as 4,4′-bipyridine, four of these 2D CPs are converted in methanol under reflux to the corresponding 2D supramolecular coordination complexes (SCCs) constructed through very strong hydrogen bonding interactions, [Cu2(4,4′-bpy)(Hsersal)2]·2H2O (7), [Cu2(4,4′-bpy)(Hser-5-OMe-sal)2]·6H2O (8), [Cu2(4,4′-bpy)(Hser-5-NO2-sal)2]·H2O (9) and [Cu2(4,4′-bpy)(Hser-5-Cl-sal)2]·4H2O·DMF (10). This chemical conversion of a CP to an SCC is unknown in the literature and indicates the hierarchical importance of coordination and hydrogen bonds in their formation. The complexes are structurally characterized by elemental analysis, UV-Vis spectroscopy, circular dichroism, IR and Raman spectroscopy, ESI mass spectrometry, single crystal and powder X-ray diffraction, polarimetry and thermogravimetric analysis. A magneto-structural correlation for the change from 1 to 7 is established through variable temperature magnetic susceptibility measurements (2–390 K) indicating strong antiferromagnetic coupling (2J = −278 cm−1) in 1 and no interaction in 7 between the Cu(II) centers. As an example, water adsorption studies of 1 and 7 were carried out to demonstrate the porous nature of the SCCs compared to the CPs.

Structural diversity of the encapsulated water clusters in the 3D supramolecular assemblies: a cyclic quasi-planar hexamer of water constructed through strong hydrogen bonding interactions

In the three-dimensional (3D) supramolecular assemblies having the general formula [Mn2(dicarboxylate)2(tpa)2]·xH2O (where tpa = N,N,N-tris(2-pyridylmethyl)-amine; dicarboxylate = acetylene dicarboxylate (adc) and x = 6 (1); fumarate and x = 8 (2) and succinate and x = 6 (3)), the dimanganese subunits differing in the dicarboxylate with a variation in the aliphatic chain structure (triple bond to double bond to single bond, respectively) provide the structural diversity of the encapsulated water clusters. These neutral supramolecular assemblies are held together by strong hydrogen bonding and π–π interactions, where the two dimensional (2D) water clusters are formed through strong hydrogen bonding (O–H⋯O). In each case, these water clusters connect the dimanganese subunits through hydrogen bonding with the uncoordinated carboxylate oxygen atoms of the dicarboxylates that bridge the Mn(II) centers of the subunit. The strength of the hydrogen bonding observed in these clusters (the range of O⋯O distances is 2.724 A to 2.845 A) is very similar to that found in water and ice. These are synthesized in high yields from a one-pot self-assembly reaction using Mn(OAc)2·4H2O, tpa and the corresponding acid in methanol at ambient conditions. Each of these is characterized by elemental analysis, single crystal and powder X-ray diffraction, IR and Raman spectroscopy and thermogravimetric analysis (TGA). Based on the X-ray crystal structures and TGA, the unusual stability of 2 compared to 1 and 3 is the result of different motifs including a cyclic quasi-planar hexamer formed through hydrogen bonding interactions. In 1 and 2, the Mn(II) centers are hexa-coordinated in a distorted octahedral geometry (N4O2), bonded to four nitrogen atoms of the ligand and two oxygen atoms from two monodentate carboxylate groups, while in 3 each Mn(II) center is heptacoordinated in a pentagonal bipyramidal geometry (N4O3), where in addition to the tpa ligand each succinate binds in chelated as well as monodentate mode, from opposite ends.

Azine-Hydrazone Tautomerism of Guanylhydrazones: Evidence for the Preference Toward the Azine Tautomer

Guanylhydrazones have been known for a long time and have wide applications in organic synthesis, medicinal chemistry, and material science; however, little attention has been paid toward their electronic and structural properties. Quantum chemical analysis on several therapeutically important guanylhydrazones indicated that all of them prefer the azine tautomeric state (by about 3-12 kcal/mol). A set of simple and conjugated azines were designed using quantum chemical methods, whose tautomeric preference toward the azine tautomer is in the range of 3-8 kcal/mol. Twenty new azines were synthesized and isolated in their neutral state. Variable temperature NMR study suggests existence of the azine tautomer even at higher temperatures with no traces of the hydrazone tautomer. The crystal structures of two representative compounds confirmed that the title compounds prefer to exist in their azine tautomeric form.

Non-hydrothermal synthesis, structural characterization and thermochemistry of water soluble and neutral coordination polymers of Zn(II) and Cd(II): precursors for the submicron-sized crystalline ZnO/CdO

Eight new water soluble and neutral one-dimensional, V-shaped coordination polymers (CPs) of Zn(II) (1–4) and Cd(II) (5–8) with a general formula of {[M2(bpxa)2(adc)2]·xH2O}n (where M(II) = Zn(II) or Cd(II); bpxa = N,N-bis(pyridylmethyl)alkyl amine; adc = acetylene dicarboxylate; x = 0 or 2) are reported. These are synthesized in good yields from the self-assembly reaction of M(OAc)2 (where M = Zn or Cd), bpxa and the corresponding acid in methanol at ambient conditions. Based on the crystal structures of 1–3 and 6–8 by single crystal X-ray diffraction studies and a subtle change in the N-alkyl group in the tridentate ligands has provided structural diversity in these CPs with respect to binding differences of the adc linker and the presence (or absence) of π–π interactions as well as the presence (or absence) of lattice water molecules, which further shows hydrogen bonding interactions between the CP chains forming supramolecular networks. These features are unique for the CPs reported in this work. All these CPs are characterized by elemental analysis and FTIR spectroscopy. The thermal stabilities of these CPs are studied by thermogravimetric analysis and variable temperature (−100 °C to +150 °C) PXRD experiments. For a proof of concept, using field-emission scanning electron microscopy (FESEM) and X-ray energy dispersive spectroscopy (EDS), one CP of each metal (3 and 7, respectively) has been shown to be a suitable precursor for generating submicron-sized crystalline ZnO or CdO at 400 °C or 250 °C, respectively. Some of the CPs were also studied for their photoluminescence properties in the solid state at room temperature.

Tuning the formation of dicarboxylate linker-assisted supramolecular 1D chains and squares of Ni(II) using coordination and hydrogen bonds

Based on the variation in the multitopic dicarboxylates differing in the aliphatic chain structure (triple bond to double bond to single bond, respectively) in the formation of diverse coordination architectures for the same metal center and the ancillary ligand bpta, three new metal organic coordination networks (MOCNs) [Ni(bpta)(adc)(H2O)2]·2H2O (2), [Ni4(bpta)4(fumarate)4(H2O)4]·4H2O (3) and [Ni(bpta)(succinate)(H2O)2]·3H2O (4) are reported here (where bpta = N,N′-bis(2-pyridylmethyl)-tert-butylamine and adc = acetylene dicarboxylate). These are synthesized in good yields from a one-pot self-assembly reaction using Ni(OAc)2, bpta and the corresponding acid in methanol at ambient conditions. In order to shed light into their formation, the intermediate compound [Ni(bpta)(OAc)2(H2O)]·H2O (1) from the two-component mixture (Ni(OAc)2 and bpta), for all MOCNs has also been isolated and crystallographically characterized. Through strong hydrogen bonding between coordinated water, uncoordinated oxygen atoms of the two acetate groups and the lattice water molecule, 1 has a 1D chain structure. In 2 and 4, only one end of the dicarboxylate is coordinated to Ni(II) due to the fact that its other end (a carboxylate group not a carboxylic acid group which is commonly found for numerous polycarboxylic acids under hydrothermal conditions) is strongly hydrogen bonded to two coordinated water molecules of the adjacent Ni(II) center of the monomeric unit generating a 1D chain which is further hydrogen bonded through the lattice water molecules to form the respective 2D supramolecular assemblies. On the other hand, bis(monodentate) syn–syn and syn–anti bridging modes of fumarates between two Ni(II) centers result in the formation of a square in 3. These squares in 3 are further associated via hydrogen bonding through the formation of a six membered hexagonal motif R64(6) between two lattice water molecules, uncoordinated oxygen atoms of the fumarate and two coordinated water molecules on Ni(II) centers. The strengths of hydrogen bonding observed in the networks of 2–4 (the range of O–O distances is 2.638 A to 2.949 A) are very similar to those found in water and ice. All these are characterized by elemental analysis, single crystal X-ray diffraction, IR and Raman spectroscopy. Their thermal behavior in the solid state analyzed by thermogravimetric analysis (TGA) shows unusual stability of 3 up to 300 °C as compared to 2 and 4.

A homochiral luminescent compound with four-fold symmetry as a potential chemosensor for nitroanilines

A homochiral compound of a dansylated amino acid ligand, [Cu2(HTyr-N-Dan)4(H2O)2]·2H2O (1) (H2Tyr-N-Dan = N-dansyltyrosine), is synthesized and crystallographically characterized. Its supramolecular chain structure is formed via intermolecular hydrogen bonding between the phenolic and the sulfato groups of the ligand while the intra-ligand π–π interactions exist between the aromatic rings of the dansyl and the tyrosine moiety of the ligand. Utilizing the luminescent property, selective sensing of nitroanilines by both the ligand and 1 is demonstrated.

Synthesis and crystal structures of low-valent binuclear vanadium complexes using the tethering ligand m-xylylenebis(acetylacetonate) (m-xba2–)

An intriguing structural type new to low-valent vanadium chemistry and the binucleating ligand m-H2xba is exhibited by the reported VIII dimers and the first structurally characterized bis(acetylacetonate) ligated complex of VII.

Capturing the structural diversification upon thermal desolvation of a robust metal organic framework via a single-crystal-to-single-crystal transformation

Using a new mixed polypyridyl–carboxylate ligand, a 2D neutral robust framework of Zn(II), {[Zn(bpaipa)]·DMF·2H2O}n (1) (where H2bpaipa = 5-(bis(pyridin-2-ylmethyl)amino)isophthalic acid), has been synthesized under solvothermal conditions in 71% yield. It undergoes single-crystal-to-single-crystal transformation upon thermal desolvation without a change in the topology of the framework where the desolvated structure shows an orientation change of an uncoordinated carboxylate oxygen atom and the pyridyl groups of the ligand within the pores. Both structures have been determined by single crystal X-ray analysis. Its high thermal stability (>350 °C) and framework integrity towards many solvents are also demonstrated by variable temperature powder X-ray diffraction and thermogravimetric analysis.

Understanding the effect of an amino group on the selective and ultrafast detection of TNP in water using fluorescent organic probes

We have designed and developed three single-molecule fluorescent probes differing in the number of amino groups, namely 5-((4,6-Diamino-1,3,5-triazin-2-yl)amino)isophthalic acid (H2ATAIA, 1), 5-((4-amino-6-methoxy-1,3,5-triazin-2-yl)amino)isophthalic acid (H2AMTAIA, 2) and 5-((4,6-dimethoxy-1,3,5-triazin-2-yl)amino)isophthalic acid (H2DMTAIA, 3), from cheap and readily available starting materials via simple procedures in high yields for demonstrating their application in highly selective and ultrafast sensing of 2,4,6-trinitrophenol (TNP) in water (slurry mode). Probes 1–3 have been characterized by various analytical techniques, such as melting point, FTIR, UV-vis and NMR (1H and 13C) spectroscopy and high resolution mass spectrometry (HRMS). It is quite evident that the effect of an amino group is more prominent compared to a methoxy group towards the selective detection of TNP over other potentially interfering nitro compounds. The detection limit for the diamino derivative was found to be 120 ppb compared to those with one amino or no amino group (0.8 ppm and 1.2 ppm, respectively). We also report the ideal real time detection of TNP through a contact mode or instant spot via paper strips. Spectral overlap, time-resolved fluorescence studies, quantum yield, Stern–Volmer plots, field emission scanning electron microscopy (FESEM) and DFT calculations have been used to establish their mechanism of action. Furthermore, competitive nitro-analyte tests demonstrate that the selectivity for TNP is more in 1 compared to 2 and 3. To the best of our knowledge, we have demonstrated for the first time molecular decoding of TNP based on the dual read-out identification scheme constructed from life-time and quantum yield. These probes have been found to be highly photostable in the presence of acidic TNP as well as recyclable without much loss of sensitivity up to five cycles. These results vividly depict that these are excellent candidates for environmental monitoring.