A crystallography-based investigation of weak interactions for drug design against COVID-19.

Interactions between proteins and small molecules play important roles in the inhibition of protein function. However, a lack of proper knowledge about non-covalent interactions can act as a barrier towards gaining a complete understanding of the factors that control these associations. To find effective molecules for COVID-19 inhibition, we have quantitatively investigated 143 X-ray crystal structures of the SARS-CoV-2 Mpro protein of coronavirus with covalently or non-covalently bound small molecules (SMs). Our present study is able to explain ordinary and perceptive aspects relating to protein inhibition. The active site of the protein consists of 21 amino acid residues, but only nine are actively involved in the ligand binding process. The H41, M49, and C145 residues have highest priority with respect to interactions with small molecules through hydrogen bond, CH-π, and van der Waals interactions. At the active site, this ranking of amino acids is clear, based on different spatial orientations of ligands, and consistent with the electronic properties. SMs with aromatic moieties that bind to the active site of the protein play a distinct role in the determination of the following order of interaction frequency with the amino acids: CH-π > H-bonding > polar interactions. This present study revealed that the G143 and C145 residues play crucial roles in the recognition of the carbonyl functionality of SMs through hydrogen bonding. With this knowledge in mind, an effective inhibitor small-molecule for SARS-CoV-2 Mpro was designed: docking studies showed that the designed molecule has strong binding affinity towards the protein. The non-covalent interactions in the protein-ligand complex are in good agreement with the results obtained from X-ray crystallography. Moreover, the present study focused on weak forces and their influence on protein inhibition, henceforth shedding much light on the essential requirements for moieties that should be present in a good inhibitor and their orientations at the ligand binding site.

Iron Complexes Anchored onto Magnetically Separable Graphene Oxide Sheets: An Excellent Catalyst for the Synthesis of Dihydroquinazoline-Based Compounds.

In this work, a green, sustainable, and efficient protocol for the syntheses of dihydroquinazoline derivatives is proposed. Initially, three Schiff base complexes of iron containing the ligand (2,2-dimethylpropane-1,3-diyl)bis(azanylylidene)bis(methanylylidene)bis(2,4-Xphenol), where X = Cl (complex 1)/Br (complex 2)/I (complex 3), were synthesized, fully characterized, and used in the desired syntheses. Complex 1 excelled as a catalyst, closely followed by complexes 2 and 3. DFT calculations helped in rationalizing the role of the halide substituent in the ligand backbone as a relevant factor in the catalytic superiority of complex 1 over complexes 2 and 3 for the synthesis of the dihydroquinazoline derivatives. Finally, to facilitate catalyst recoverability and reusability, complex 1 was immobilized on GO@Fe3O4@APTES (GO, graphene oxide; APTES, 3-aminopropyltriethoxysilane) to generate GO@Fe3O4@APTES@FeL1 (GOTESFe). GOTESFe was thoroughly characterized through scanning electron microscopy, transmission electron microscopy, powder X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis, and X-ray photoelectron spectroscopy and efficiently used for the synthesis of dihydroquinazoline derivatives. GOTESFe could be magnetically recovered and reused up to five cycles without compromising its catalytic efficiency. Therefore, immobilization of the chosen iron complex onto magnetic GO sheets offers an extremely competent route in providing a blueprint of a readily recoverable, reusable, robust, and potent catalyst for the synthesis of dihydroquinazoline-based compounds.

A Chemodosimetric Approach for Fluorimetric Detection of Hg2+ Ions by Trinuclear Zn(II)/Cd(II) Schiff Base Complex: First Case of Intermediate Trapping in a Chemodosimetric Approach.

The present work discloses the application of two fluorescent zinc and cadmium complexes (1 and 2) for sensing of Hg(II) ions through a chemodosimetric approach. The ligand under consideration in this work is a N2O donor Schiff base ligand (E)-4-bromo-2-(((2-morpholinoethyl)imino)methyl)phenol (HL), which has been harnessed to generate complexes [Zn3L2(OAc)4] (1) and [Cd3L2(OAc)4] (2). X-ray single crystal diffraction studies unveil the trinuclear skeleton of complexes 1 and 2. Both complexes have been found to be highly fluorescent in nature. However, the quantum efficiency of Zn(II) complex (1) dominates over the Cd(II) analogue (2). The absorption and emission spectroscopic properties of the complexes have been investigated by density functional theory. Complexes 1 and 2 can detect Hg2+ ions selectively by fluorescence quenching, and it is noteworthy to mention that the mechanism of sensing is unique as well as interesting. In the presence of Hg2+ ions, complexes 1 and 2 are transformed to mononuclear mercuric intermediate complex (3) and finally to a trinuclear mercuric complex (4) by hydrolysis. We have successfully trapped the intermediate complex 3, and we characterized it with the aid of X-ray crystallography. Transformation of complexes 1 and 2 to intermediate complex 3 and finally to 4 has been established by UV-vis spectroscopy, fluorescence spectroscopy, ESI-MS spectroscopy, 1H NMR spectroscopy, and X-ray crystallography. The spontaneity of the above conversion is well supported by thermodynamic aspects as reflected from density functional theoretical calculations.

Exploration of catecholase-like activity of a series of magnetically coupled transition metal complexes of Mn, Co and Ni: new insights into the solution state behavior of Mn complexes.

A series of tri-nuclear complexes of general formula [M3L2(OAc)4], where M = Mn (1), Co (2) and Ni (3), (HL = (E)-4-bromo-2-(((2-morpholinoethyl)imino)methyl)phenol), have been synthesized. Single crystal X-ray crystallography reveals that each molecule contains three metal ions which are bridged by four acetate moieties. In the solution phase, the complexes are present as mononuclear species. Amongst them, the manganese atom of complex 1 switches its oxidation state from +ii to +iii with time, as confirmed by time dependent UV-Vis and EPR spectroscopic techniques. Furthermore, complex 1 with Mn in both oxidation states can oxidise 3,5-DTBC to 3,5-DTBQ through the ligand centred radical formation pathway. It is remarkable that complex 1 in the MnII oxidation state shows an abnormally high rate constant value in the oxidation of 3,5-DTBC to 3,5-DTBQ. This difference in rate constant values for catechol oxidation reaction by complex 1 can be explained by considering the binding constant value of catechol with MnII and MnIII respectively from experimental and theoretical aspects. Similar to complex 1, complexes 2 and 3 also catalyse catechol oxidation following ligand centred imine radical formation pathways. Furthermore, magnetic properties of all the complexes were explored. DC magnetic susceptibility studies of complexes 1 and 2 revealed that in both the complexes the metal centres are antiferromagnetically coupled with adjacent metal centres, whereas in the case of complex 3, weak ferromagnetic interaction occurs between the neighbouring NiII centres at low temperature.

Surfactant-Mediated Solubilization of Magnetically Separable Nanocatalysts for the Oxidation of Alcohols.

Cetrimonium bromide (CTAB)-coated water disperse magnetically separable nanocatalysts CTAB/Fe3O4@dopa@ML (M = Fe or Mn, L = cyclohexane-1,2-diylbis(azanylylidene)bis(methanylylidene)bis(2,4-diXphenol; X = Cl, Br, and I) have been synthesized using a simple synthetic strategy. This approach provides a new fruitful strategy to reduce the leaching of the active metal complex from the catalyst surface to the aqueous media. The synthesized catalysts have been found to be excellent for oxidation of alcohols in aqueous medium at room temperature. A probable catalytic pathway involving the generation of hydroperoxo intermediates has been assumed, and these intermediates have been characterized using density functional theory and several spectroscopic techniques. It is worthy of mention that the synthesized CTAB-coated magnetically separable nanocatalysts can be magnetically recovered from the aqueous reaction mixture after more than five cycles, which renders this approach as a sustainable and accessible one.

Unique mononuclear Mn(II) complexes of an end-off compartmental Schiff base ligand: experimental and theoretical studies on their bio-relevant catalytic promiscuity.

Three new mononuclear manganese(ii) complexes, namely [Mn(HL)2]·2ClO4 (1), [Mn(HL)(N(CN)2)(H2O)2]·ClO4 (2) and [Mn(HL)(SCN)2] (3) [LH = 4-tert-butyl-2,6-bis-[(2-pyridin-2-yl-ethylimino)-methyl]-phenol], have been synthesized and structurally characterized. An "end-off" compartmental ligand (LH) possesses two symmetrical compartments with N2O binding sites but accommodates only one manganese atom instead of two due to the protonation of the imine nitrogen of one compartment. Although all three complexes are mononuclear, complex 1 is unique as it has a 1 : 2 metal to ligand stoichiometry. The catalytic promiscuity of complexes 1-3 in terms of two different bio-relevant catalytic activities namely catecholase and phenoxazinone synthase has been thoroughly investigated. EPR and cyclic voltametric studies reveal that radical formation rather than metal centered redox participation is responsible for their catecholase-like and phenoxazinone synthase-like catalytic activity. A computational approach suggests that imine bond bound radical generation rather than phenoxo radical formation is most likely responsible for the oxidizing properties of the complexes.