Unraveling topoisomerase IA gate dynamics in presence of PPEF and its preclinical evaluation against multidrug-resistant pathogens.

Type IA topoisomerases maintain DNA topology by cleaving ssDNA and relaxing negative supercoils. The inhibition of its activity in bacteria prevents the relaxation of negative supercoils, which in turn impedes DNA metabolic processes leading to cell death. Using this hypothesis, two bisbenzimidazoles, PPEF and BPVF are synthesized, selectively inhibiting bacterial TopoIA and TopoIII. PPEF stabilizes the topoisomerase and topoisomerase-ssDNA complex, acts as an interfacial inhibitor. PPEF display high efficacy against ~455 multi-drug resistant gram positive and negative bacteria. To understand molecular mechanism of inhibition of TopoIA and PPEF, accelerated MD simulation is carried out, and results suggested that PPEF binds, stabilizes the closed conformation of TopoIA with -6Kcal/mol binding energy and destabilizes the binding of ssDNA. The TopoIA gate dynamics model can be used as a tool to screen TopoIA inhibitors as therapeutic candidates. PPEF and BPVF cause cellular filamentation and DNA fragmentation leading to bacterial cell death. PPEF and BPVF show potent efficacy against systemic and neutropenic mouse models harboring E. coli, VRSA, and MRSA infection without cellular toxicity.

Unraveling the Origin of Differentiable 'Turn-On' Fluorescence Sensing of Zn2+ and Cd2+ Ions with Squaramides.

A squaramide ring conjugated with Schiff-bases decorated with hydroxy and methoxy functional groups differentially senses zinc and cadmium ions, which turn on the fluorescence. The feebly emitting free ligands light up in the presence of zinc and cadmium acetates, with the acetate ion playing a pivotal role as a conjugate anion. The selective and differentiable emission responses for zinc and cadmium ions make these ligands efficient multi-analyte sensing agents. Furthermore, these ligands could be used to differentially sense zinc and cadmium ions even in aqueous environments. The NMR investigations reveal marginal differences in the binding of zinc and cadmium ions to the ligands, whereas density functional theory calculations suggest the different extent of ligand-to-metal charge transfer (LMCT) contributes to the differential behavior. Finally, comparison of the excited-state dynamics of free ligand and the metal complexes reveal the appearance of longer lifetime (about 500-700 ps) component with complexation, due to rigidified molecular skeleton, thereby impeding the non-radiative processes.

Synthesis and structure of arylselenium(ii) and aryltellurium(ii) cations based on rigid 5-tert-butyl-1,3-bis-(N-pentylbenzimidazol-2'-yl)benzenes.

The transmetalation reactions of a mercury precursor, [Pentyl(N^C^N)HgCl] (19), with selenium halides (SeCl4, SeBr4, and SeCl2) were attempted to obtain the corresponding organoselenium trichloride [Pentyl(N^C^N)SeCl3], tribromide [Pentyl(N^C^N)SeBr3], and monochloride [Pentyl(N^C^N)SeCl], respectively [(N^C^N) = 5-tert-butyl-1,3-bis-(N-pentyl-benzimidazol-2'-yl)phenyl]. However, in all the cases, a very facile ionization of the Se-halogen bond was observed leading to the isolation of a new class of air stable arylselenium(ii) complexes: [Pentyl(N^C^N)Se+]2[HgCl4]2- (20) and [Pentyl(N^C^N)Se+]2[HgBr4]2- (21). This is the first report on the formation of NCN pincer-based arylselenium(ii) cations via the transmetalation route. Similar reactions were further investigated with several tellurium precursors: {TeCl4, TeBr4 and TeI2} which resulted in the formation of analogous aryltellurium(ii) complexes: [Pentyl(N^C^N)Te+]2[HgCl4]2- (22), [Pentyl(N^C^N)Te+][Cl]- (23), [Pentyl(N^C^N)Te+]2[HgBr4]2- (24), [Pentyl(N^C^N)Te+][Br]- (25) and [Pentyl(N^C^N)Te+]4[Hg2Cl4.72I3.28]4- (26). These are only the second set of examples of aryltellurium cations (hypervalent 10-Te-3 species) with the NCN pincer-based ligand, characterised by X-ray crystallographic studies. The crystallographic studies show a strong SeN/TeN intramolecular interaction, which is confirmed by NBO calculations suggesting the donation of a lone pair of electrons on nitrogen to a lone p-vacancy on selenium/tellurium atoms. The analysis based on NPA derived charges indicates that the contribution of SeN interactions to the electrostatic stabilization energy is in the range of 40-60%, whereas TeN interactions have a contribution of about 84% and more, attributed to the differences in the electronegativity of selenium and tellurium. Furthermore, the formation of arylselenium(ii) and aryltellurium(ii) complexes was favoured due to the presence of the σ-hole on the Se/Te centres.

Insights into acid dissociation of HCl and HBr with internal electric fields.

The electric field experienced by an acid molecule in the acid-water cluster depends on its local environment comprising of surrounding water molecules. A critical field of about 193 and 163 MV cm-1 is required for the dissociation of HCl and HBr, respectively, and is associated with the arrangement of water molecules around the acid. The critical field required for dissociation of isolated HCl and HBr is 510 and 462 MV cm-1, respectively. Hence the solvation of the proton and the halide anion by water molecules substantially lowers the critical electric field by about 300 MV cm-1, relative to vacuum.

Internal electric fields in small water clusters [(H2O)n; n = 2-6].

The electric field experienced by a water molecule within a water cluster depends on its position relative to the rest of the water molecules. The stabilization energies and the red-shifts in the donor O-H stretching vibrations in the water clusters increase with the cluster size concomitant with the increase in the electric field experienced by the donor O-H of a particular water molecule due to the hydrogen bonding network. The red-shifts in O-H stretching frequencies show a spread of about ±100 cm(-1) against the corresponding electric fields. Deviations from linearity were marked in the region of 100-160 MV cm(-1), which can be attributed to the strain in the hydrogen bonding network, especially for structures with DDAA and DDA motifs. The linear Stark effect holds up to 200 MV cm(-1) of internal electric field for the average red-shifts in the O-H stretching frequencies, with a Stark tuning rate of 2.4 cm(-1) (MV cm(-1))(-1), suggesting the validity of the classical model in small water clusters.