Intimate binding mechanism and structure of trigonal nickel(I) monocarbonyl adducts in ZSM-5 zeolite-spectroscopic continuous wave EPR, HYSCORE, and IR studies refined with DFT quantification of disentangled electron and spin density redistributions along σ and π channels.

Interaction of tetracoordinated nickel(I) centers generated inside the channels of ZSM-5 zeolite with carbon monoxide ((12,13)CO, pCO < 1 Torr) led to the formation of T-shaped, top-on monocarbonyl adducts with a unique trigonal nickel core, supported by two oxygen donor ligands. The mechanism of the formation of the {Ni(I)-CO}ZSM-5 species was accounted for by a quantitative molecular orbital correlation diagram of CO ligation. Detailed electronic and magnetic structure of this adduct was obtained from comprehensive DFT calculations, validated by quantitative reproduction of its continuous wave electron paramagnetic resonance (CW-EPR), hyperfine sublevel correlation (HYSCORE), and IR fingerprints, using relativistic Pauli and ZORA-SOMF/B3LYP methods. Molecular analysis of the stretching frequency, νCO = 2109 cm(-1), g and A((13)C) tensors (g(xx) = 2.018, g(yy) = 2.380, g(zz) = 2.436, A(xx) = +1.0 ± 0.3 MHz, A(yy) = -3.6 ± 0.9 MHz, A(zz) = -1.6 ± 0.3 MHz) and Q((27)Al) parameters (e(2)Qq/h = -13 MHz and η = 0.8) supported by quantum chemical modeling revealed that the Ni-CO bond results from the π overlap between the low-laying π(2p) CO states with the 3d(xz) and 3d(yz) orbitals, with a small σ contribution due to the overlap of σ(2p+2s) orbital and a protruding lobe of the in-plane 3d(xz) orbital. Two types of orbital channels (associated with the σ and π overlap) of the electron and spin density flows within the {Ni(I)-CO} unit were identified. A bathochromic shift of the νCO stretching vibration was accounted for by resolving quantitatively the separate contributions due to the σ donation and π back-donation, whereas the (13)C hyperfine coupling was rationalized by incongruent α and ß spin flows via the σ and π channels. As a result the very nature of the carbon-metal bond in the Ni(I)-CO adduct and the molecular backbone of the corresponding spectroscopic parameters were revealed with unprecedented accuracy.

Probing a chemical space for fragmental topology-activity landscapes (FRAGTAL): application for diketo acid and catechol HIV integrase inhibitor offspring fragments.

Fragmental topology-activity landscapes (FRAGTAL), a new concept for encoding molecular descriptors for fragonomics into the framework of the molecular database records is presented in this paper. Thus, a structural repository containing biological activity data was searched in a substructure mode by a series of molecular fragments constructed in an incremental or decremental manner. The resulted series of database hits annotated with their activities construct FRAGTAL descriptors encoding a frequency of the certain fragments among active compounds and/or their activities. Actually, this method might be interpreted as a simplified adaptation of the frequent subgraph mining (FSM) method. The FRAGTAL method reconstructs the way in which medicinal chemists are used to designing a prospective drug structure intuitively. A representative example of the practical application of FRAGTAL within the ChemDB Anti-HIV/OI/TB database for disclosing new fragments for HIV-1 integrase inhibition is discussed. In particular, FRAGTAL method identifies ethyl malonate amide (EMA) as the diketo acid (DKA) related arrangement. Since new molecular constructs based on the EMA fragment are still a matter of future investigations we referred to this as anthe DKA offspring.

Ethyl malonate amides: a diketo acid offspring fragment for HIV integrase inhibition.

While searching for new HIV integrase inhibitors we discovered that some ethyl malonate amides (EMA) are active against this enzyme. Surprisingly, the main function can only very rarely be found among the reported drug candidates. We synthesised a series of compounds in order to establish and analyse the structure-activity relationship. The similarity to the important classes of HIV integrase inhibitors as well as the synthetic availability of the different targets including this pharmacophore makes EMA compounds an interesting object of investigations.

Investigating the anti-proliferative activity of styrylazanaphthalenes and azanaphthalenediones.

A group of styrylazanaphthalenes and azanaphthalenediones were synthesized and tested for their anti-proliferative activity. Most of the compounds were obtained with the use of microwave-assisted synthesis. The lipophilicity of the compounds was measured by RP-HPLC and their anti-proliferative activity was assayed against the human SK-N-MC neuroepithelioma and HCT116 human colon carcinoma cell lines. Active compounds were also tested in clonogenity and comet assays. Several quinazolinone and styrylquinazoline analogues were found to have markedly greater anti-proliferative activity than desferoxamine and cis-platin.