Quantum chemical and physicochemical influences on structure–activity relations and drug design

Quantum chemical results will be presented on drugs, carcinogens, teratogens, and endogenous biomolecules using our new nonempirical ab initio MODPOT /VRDDO method, which incorporates as options to our ab initio LCAO -MO -SCF /CI programs ab initio effective core model potentials (MODPOT ) permitting one to calculate only the valence electrons explicitly yet accurately and an integral prescreening technique (VRDDO , variable retention of diatomic differential overlap) especially effective for spatially extended molecules. For molecules of the size of those of interest the MODPOT /VRDDO calculations run an order-of-magnitude faster than with our own fast ab initio programs and still retain accuracy to the third decimal place for the valence electron properties. We have also just implemented a new efficient MERGE technique which allows us to reuse integrals from a common skeletal fragment and only to have to recalculate those for a new atom or group or a change in its position. Examples will be presented of the use of this technique on a carcinogenic polycyclic aromatic hydrocarbon and its metabolites. The pK_a's, oil-water partition, and drug distribution coefficients as a sensitive function of pH have been measured for a number of drugs as well as for relevant endogenous biomolecules. The pH dependence of the lipophilicities of such molecules has profound implication on appropriate use of such data in QSAR studies.     

Brominaed β-carbolines from the marine hydroid linnaeus

Three new brotminated β-carbolines (1–3) have been isolated from the lipophylic extract of the marine hydroid Linnaeus and their structures determined on the basis of spectral data including two dimensional proton-carbon shift correlation (direct and long range) NMR spectroscopy. The syntheses of compounds 1–3, starting from the appropriate brominated tryptophan derivatives, are also described.     

A new synthesis of α-substituted δ-carbolines

The paper describes a new general synthesis of α-substituted δ-carbolines based on key steps such as metalation, cross-coupling and cyclization.     

The structure–activity relationship of some hexacoordinated dimethyltin(IV) complexes of fluorinated β‐diketone/β‐diketones and sterically congested heterocyclic β‐diketones

The study was focused on the structure–activity relationship of some newly synthesized hexacoordinated dimethyltin(IV) complexes of fluorinated β‐diketone/β‐diketones and sterically congested heterocyclic β‐diketones. These complexes were screened for their antibacterial activity against a Gram‐negative bacterium (Pseudomonas aeruginosa) and Gram‐positive bacteria (Streptomyces griseus, Staphylococcus aureus, Bacillus subtilis) and the results were compared with those of a standard antibacterial drug. Some of the complexes were also screened for their antifungal activity against various fungi (Aspergillus niger, A. flavus, Trichoderma viride, Fusarium oxysporum) and were found to be active. These new hexacoordinated complexes of dimethyltin(IV) were generated by reactions of dimethyltin(IV) dichloride and sodium salts of fluorinated β‐diketone/β‐diketones and sterically congested heterocyclic β‐diketones in 1:1:1 molar ratio in refluxing dry benzene. Plausible structures of these complexes were suggested with the aid of physicochemical and spectroscopic studies. ¹¹⁹Sn NMR spectral data revealed the presence of a hexacoordinated tin centre in these dimethyltin(IV) complexes. Copyright © 2015 John Wiley & Sons, Ltd.     

Retention of some monoamine oxidase inhibitory drugs on a β-cyclodextrin polymer-coated silica column

The retention of seventeen monoamine oxidase inhibitory drugs (mono- and disubstituted derivatives of propargylamine) was determined on a β- cyclodextrin polymer (β-CDP)-coated silica column using methanol-0.05 M K₂HPO₄ (6:4, v/v) as the eluent. The inclusion complex formation between the drugs and a water-soluble β-cyclodextrin polymer was studied by charge-transfer chromatography carried out on reversed- phase TLC layers. The capacity factors were correlated with the various physico-chemical parameters and with the inclusion complex-forming capacity of the monoamine oxidase inhibitory drugs. Calculations indicated that the inclusion complex-forming capacity of the drugs does not influence their retention on a β-CDP column, that is, the water-soluble and water-insoluble β-CDPs show different retention characteristics. The specific hydrophilic adsorption surface of the solutes significantly influences the retention in HPLC. The results suggest that the selectivity of the β-CDP-coated silica support may be different from that of the traditional alkyl-bonded reversed-phase columns.     

A meso–meso β‐β β‐β Triply Linked Subporphyrin Dimer

A meso–meso β‐β β‐β triply linked subporphyrin dimer 6 was synthesized by stepwise reductive elimination of β‐to‐β doubly Pt^II‐bridged subporphyrin dimer 9 . Dimer 6 was characterized by spectroscopic and electrochemical measurements, theoretical calculations, and picosecond time‐resolved transient absorption spectroscopy. X‐ray diffraction analysis reveals that 6 has a bowl‐shaped structure with a positive Gaussian curvature. Despite the curved structure, 6 exhibits a remarkably red‐shifted absorption band at 942 nm and a small electrochemical HOMO–LUMO gap (1.35 eV), indicating an effectively conjugated π‐electronic network.     

Molecular structure–biological activity relationships on the basis of quantum-chemical calculations

Detailed quantum-chemical calculations by means of semiempirical all-valence electrons methods and a generalized (multivariable) rank correlation analysis are the fundamentals of a novel strategy of search for QSAR within homologous series of compounds. The set of molecular parameters (describing the electronic and conformational properties as well as potential interactions of the drugs) is calculated theoretically. Owing to the rank correlation method, no linear model (like LFER ) for the dependence of the biological activity upon the molecular parameters is presumed. The computed correlation coefficients are valued by carefully determined levels of statistical significance. Significant correlations are used to predict unknown activities in terms of ranks relative to the basic sample.     

Methods of studies on quantitative structure–activity relationships for chiral compounds

Chiral compounds are very important in drug development, organic synthesis, materials science, toxicology, or environmental chemistry. Therefore, for creating new drugs, several methods have been suggested in recent years. In several laboratories in the world, some new methods for the derivations of the parameters were constructed and used for studies on quantitative structure–activity/property relationships of chiral molecules. The algorithms reviewed in this paper involve Zargeb group chiral indices, chiral molecular connectivity index, chiral topological charge index, chiral A_m index, chiral indices based on the matrixes, chiral indices based on chiral product, conformation‐independent chirality code, conformation‐dependent chirality code, quantitative two‐dimensional chirality degrees of benzenoids, and so on. Copyright © 2012 John Wiley & Sons, Ltd.     

Planarity of heteroaryldithiocarbazic acid derivatives showing tuberculostatic activity: structure–activity relationships

The search for new tuberculostatics is an important issue due to the increasing resistance of Mycobacterium tuberculosis to existing agents and the resulting spread of the pathogen. Heteroaryldithiocarbazic acid derivatives have shown potential tuberculostatic activity and investigations of the structural aspects of these compounds are thus of interest. Three new examples have been synthesized. The structure of methyl 2‐[amino(pyridin‐3‐yl)methylidene]hydrazinecarbodithioate, C₈H₁₀N₄S₂, at 293 K has monoclinic (P2₁/n) symmetry. It is of interest with respect to antibacterial properties. The structure displays N—H…N and N—H…S hydrogen bonding. The structure of N′‐(pyrrolidine‐1‐carbonothioyl)picolinohydrazonamide, C₁₁H₁₅N₅S, at 100 K has monoclinic (P2₁/n) symmetry and is also of interest with respect to antibacterial properties. The structure displays N—H…S hydrogen bonding. The structure of (Z)‐methyl 2‐[amino(pyridin‐2‐yl)methylidene]‐1‐methylhydrazinecarbodithioate, C₉H₁₃N₄S₂, has triclinic (P) symmetry. The structure displays N—H…S hydrogen bonding.     

Reissert compound studies. XLII. Synthesis and reactions of the 3,4-dihydro-β-carboline reissert compound and observations on α, β, and γ-carbolines

3,4-Dihydro-β-carboline and benzo[α]-γ-carboline yielded Reissert compounds. The 3,4-dihydro-β-carboline Reissert compound, through its acid- and base-promoted reactions, was found to be a very useful intermediate in the synthesis of several β-carboline derivatives including tetracyclic compounds. Reaction of the 3,4-dihydro-β-carboline Reissert compound with dichlorodicyanobenzoquinone (DDQ) resulted in the formation of l-cyano-β-carboline thereby providing the first example of an oxidation of a Reissert compound with DDQ. α-, β- and γ-Carbolines failed to form Reissert compounds under a wide variety of conditions. 7-Azaindole also failed to yield a Reissert compound.     

Electric-field mapping of some substituted 3-pyridinecarboxylic acid cardiotonics and the possible structure–activity relationships

Four esters of 5-cyano-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid involving substitutions of methyl, isopropyl, tert-butyl, and phenyl groups at the 2-position, which exhibit varying degrees of cardiotonic activities, have been studied using the electric-field and electrostatic potential mapping techniques. The net charge distributions in the molecules were obtained using the MNDO method. Electric-field mapping has been performed in three-dimension in order to obtain information about the possible structure–activity relationships of these compounds. The results show a prominent electric-field region in the methyl-substituted compound extending from near the oxygen atom O₆ to near the methyl group. This fact and orientation of the electric field in this region, in view of the Erhardt model, may be related to the greater cardiotonic activity of the methyl-substituted molecule in comparison to those of the other molecules of this class. © 1992 John Wiley & Sons, Inc.     

Structure–reactivity relationships of alkyl α‐hydroxymethacrylate derivatives

A series of alkyl α‐hydroxymethacrylate derivatives with various secondary functionalities (ether, ester, carbonate, and carbamate) and terminal groups (alkyl, cyano, oxetane, cyclic carbonate, phenyl and morpholine) were synthesized to investigate the effect of intermolecular interactions, H‐bonding, π–π interactions, and dipole moment on monomer reactivity. All of the monomers except one ester and one ether derivative are novel. The polymerization rates, determined by using photo‐DSC, showed the average trend (aromatic carbamate > hydroxyl > ester > carbonate ～ aliphatic carbamate ～ ether), with several exceptions due to the differences in terminal groups. There is a correlation between the chemical shift differences of the double bond carbons, the calculated dipole moments, and the reactivities only for nonhydrogen bonded monomers. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

γ–α Solid–solid transition of isotactic polypropylene

X-ray diffraction patterns have been taken as a function of time and temperature on a sample of polypropylene held under high pressure (4.14 kbar) for 180 hr. at a temperature of 248°C. and subsequently cooled to room temperature. The molded sample initially crystallizes in the triclinic γ–phase but transforms to the γ–phase at elevated temperatures. The rate of conversion from γ to α is a function of time and temperature and tends to approach a constant value with increasing time. The nature of the thermal changes occurring in the sample was also studied by differential scanning calorimetry. It appears that at low scan speeds, there is a solid–solid transformation from the α-phase to the γ–phase, but at high scan speeds, the γ–phase melts without conversion to the α-phase.     

α–γ transition in nylon 6

The α to γ transition that occurs in nylon 6 upon iodine treatment was investigated by infrared spectroscopy, differential thermal analysis, and x-ray diffraction techniques. Thin films of nylon (0.2 mil) were treated in either iodine–potassium iodide aqueous solution or in iodine vapor. Very short treatment times, in the order of 30 sec, were found to effect the transition when a solution 0.5M with respect to iodine was used. The infrared spectra of the iodine nylon complexes formed from either the α- or γ-nylon 6 treated in vapor or dissolved iodine were all similar. This is an indication that molecular iodine is the active species in forming the complex. The temperature of the washing solution used to remove the iodine from the nylon determines whether an α-nylon 6 or γ-nylon 6 is obtained from the complex after washing. Nylon 6 plaque surfaces and thin films are similar in their behavior towards the iodine treatment. The γ-nylon 6 is a stable modification at all temperatures below its melting point. The conversion of the γ form back to the α modification can occur only if the hydrogen bonding is severely affected, e.g., by phenol treatment, iodine treatment, melting, etc. Infrared spectroscopy provided no evidence for an α–γ transition in nylon 6 on heating the sample continuously through its melting point. The shapes of the melting peaks in the above two modifications of nylon 6 were sufficiently different to provide a means of identifying the two crystalline forms.