Kunal Kumar Jha

Isostructural polymorphs: qualitative insights from energy frameworks

Three isostructural polymorphs with two-dimensional and three-dimensional similarities are demonstrated quantitatively from similarity relationship analysis. The similarity dimensions are then visualized and correlated in a novel way via qualitative analysis using ‘energy frameworks’. Two of the three polymorphs with three-dimensional similarities exhibiting identical physical properties have almost equi-energetic crystal structures while the most stable third polymorph exhibits distinct properties. Thereby, structure–property correlations are derived, both quantitatively and qualitatively.

Reciprocal carbonyl–carbonyl interactions in small molecules and proteins

Carbonyl-carbonyl n→π* interactions where a lone pair (n) of the oxygen atom of a carbonyl group is delocalized over the π* orbital of a nearby carbonyl group have attracted a lot of attention in recent years due to their ability to affect the 3D structure of small molecules, polyesters, peptides, and proteins. In this paper, we report the discovery of a “reciprocal” carbonyl-carbonyl interaction with substantial back and forth n→π* and π→π* electron delocalization between neighboring carbonyl groups. We have carried out experimental studies, analyses of crystallographic databases and theoretical calculations to show the presence of this interaction in both small molecules and proteins. In proteins, these interactions are primarily found in polyproline II (PPII) helices. As PPII are the most abundant secondary structures in unfolded proteins, we propose that these local interactions may have implications in protein folding.Carbonyl-carbonyl π* non covalent interactions affect the structure and stability of small molecules and proteins. Here, the authors carry out experimental studies, analyses of crystallographic databases and theoretical calculations to describe an additional type of carbonyl-carbonyl interaction.

Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors.

A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50 values. This molecular library was designed via intuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human topoisomerase 1 (HTop1) and Leishmania donovani topoisomerase 1(LdTop1). The most active compound 4 displayed no cytotoxicity against normal mammalian COS7 cell line (~100 fold less inhibition at the EC50). Similar to camptothecin, 4 interacted with free LdTop1 as observed in the preincubation DNA relaxation inhibition experiment. It also displayed anti-protozoal activity against Leishmania donovani promastigote. Crystal structure investigation of 4 and its molecular modelling with LdTop1 revealed putative binding sites in the enzyme that could be harnessed to generate molecules with better potency.

Substituted furopyridinediones as novel inhibitors of α-glucosidase

The global preponderance of diabetes mellitus has prompted the medical community to opt for various therapeutic solutions to curb this menace. One of the means involved controlling the post prandial hyperglycemia. α-Glucosidase inhibitors are known to be excellent agents for controlling postprandial hyperglycemia. Different classes of α-glucosidase inhibitors have been discovered. In this context, a diverse library of substituted furopyridinediones (12a–v) was designed as potential inhibitors of α-glucosidase, using an intuitive scaffold hopping approach (which was further rationalized by molecular docking). They were synthesized in one step via an aldol condensation reaction of the furopyridinedione scaffold and appropriate aldehydes. The compounds were screened against α-glucosidase using acarbose as the reference inhibitor. Among the screened compounds, 12p transpired to be the lead candidate with an IC50 of 0.24 μM. Lineweaver–Burke analysis of 12p indicated that it is a mixed inhibitor. X-ray crystallography of 12p further confirmed its structure. Molecular modelling studies and molecular dynamic simulation experiments were performed against a homology model of α-glucosidase to observe the binding interaction of 12p with the enzymes.

Is it Reasonable to Obtain Information on the Polarizability and Hyperpolarizability Only from the Electron Density

Formulae for the static electronic polarizability and hyperpolarizability are derived in terms of moments of the ground-state electron density matrix by applying the Unsold approximation and a generalization of the Fermi-Amaldi approximation. The latter formula for the hyperpolarizability appears to be new. The formulae manifestly transform correctly under rotations, and they are observed to be essentially cumulant expressions. Consequently, they are additive over different regions. The properties of the formula are discussed in relation to others that have been proposed in order to clarify inconsistencies. The formulae are then tested against coupled-perturbed Hartree-Fock results for a set of 40 donor-π-acceptor systems. For the polarizability, the correlation is reasonable; therefore, electron density matrix moments from theory or experiment may be used to predict polarizabilities. By constrast, the results for the hyperpolarizabilities are poor, not even within one or two orders of magnitude. The formula for the two- and three-particle density matrices obtained as a side result in this work may be interesting for density functional theories.

Efficient organic NLO material: charge-density analysis and device fabrication

Organic scaffolds such as nitro stilbene having π-eˉ donor (D) acceptor (A) substituents facilitates inter/intra-molecular charge transfer, leading to the generation of good frequency conversion materials [1]. The interactions such as C—H•••O, C —H•••π, C—H•••N etc. present in such D-π-A system act as a channel for intermolecular charge transfer. Further, the presence of non-centric crystal field facilitates the charge transfer and hence the dipolar interactions; leads to the enhancement of dipole moment. Such D-π-A systems in crystalline form having dense molecular packing serve as a good candidate for high mobility charge transport diode and field effect transistor [2]. In this direction, here we report the case of (Z)-3-(4-(dimethylamino)phenyl)-2-(4-nitrophenyl)acrylonitrile (NNDM_CNS), a cyano-substituted nitro stilbene derivative belongs to the family of D-π-A chromophore and crystallized in non-centrosymmetric space group, Pn. Detailed charge density analysis [3] based on both high resolution (sin θ/λ = 1.1 Åˉ1) X-ray diffraction data and theoretical structure factors derived via periodic calculations followed by topological analysis of intermolecular interactions and examination of electrostatic potential maps helped understanding the charge transfer mechanism in this system. Further, the intramolecular charge transfer states were experimentally observed in its emission spectra. Nonlinear optical (NLO) activity measurement and in-crystal NLO property calculations confirmed that this organic material is indeed a potential NLO material. Furthermore, the material was characterized for its charge transport properties and applications in organic electronic devices. The space charge limited current (SCLC) measurements were carried out using Ag/NNDM_CNS-single crystal/Ag and Cu/NNDM_CNSsingle crystal/Cu based electron-only and hole-only diodes, respectively. Additionally, Cu/NNDM_CNS-single crystal/Ag diode was fabricated and tested to study its bipolar charge transport characteristics. The combination of experimental and theoretical analyses along with complementary solution based and in-crystal studies suggest that this organic NLO material indeed an efficient charge transport material and it found to exhibit appropriate properties. [1] Vrcelj, R.M. et al. (2002), Cryst. Growth Des. 2, 609-617. [2] Liu, J. et al. (2015), Nat. Comm. 6, 10032. [3] Hansen, N. K. and Coppens, P. (1978) Acta Cryst. A34, 909-921.

Exploring Charge Transfer Mechanism in Organic NLO (Polymorphic) Materials

The understanding of nonlinear polarization mechanism and their relation to the structural characteristics of non-linear optical (NLO) materials have been utmost importance considering a surge in the information technology and industrial applications. Some investigations in search of NLO materials have been carried out on organic molecule scaffolds such as stilbene and chalcone having πeˉ donor acceptor substituent which facilitates intermolecular charge transfer; leading to the generation of good frequency conversion materials. Few of such materials are known to exhibit polymorphic characters and most of which crystallize in noncentrosymmetric space group – necessity for a NLO material. It has been realized that the chirality, polymorphic character and NLO activity of the chalcone derivatives are mainly governed by both the substitutions at the para position and the position of sulfur atom in the thiophene ring of thienylchalcone. This presentation will highlight the preliminary results towards the analyses of electron density distributions on NLO active stilbene and chalcone derivatives and their polymorphic forms. Therefore, explore the charge transfer mechanism responsible for the variation of NLO activity across these systems and on their non-centrosymmetric polymorphic forms. Charge densities modelled using both multipole formalism (Hansen & Coppens, 1978) and X-ray constraint wavefunction fittings (Jayatilaka & Grimwood, 2001) will be considered for these studies.