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The application of quantitative structure–activity relationships to the understanding of psychotropic activity is briefly reviewed.

Monocyclic aromatic amines (MAAs) are environmental pollutants. Many of them are genotoxic and impose hazards to human health. The mutagenicity of more than 80 of these amines was reviewed with primary emphasis on evaluation by the Ames Salmonella/microsome testing system. Many amines are mutagenic in Salmonella tester strains TA98 and TA100, but S9 mix is required for activity for most of the active ones. 2,4-Diaminotoluene, 2,4-diaminoethylbenzene, and a few amines containing a nitro-group are direct mutagens. There are several quantitative structure–activity relationship (QSAR) models which rationalize mutagenicity of many aromatic amines and several parameters, such as the lowest unoccupied molecular orbital energy (ELUMO), highest occupied molecular orbital energy (EHOMO), and hydrophobicity that are important. What factors determine the minimum requirement for the compound to be mutagenic and what factors determine the extent of mutagenicity suggest questions for further study.

Quantitative structure-retention relationships (QSRRS) were compared for a set of 1,4-benzodiazepine (BDZ) test solutes analyzed by high-performance liquid affinity chromatography (HPLAC), reversed-phase (RP) and adsorption (normal-phase, NP) high-performance liquid chromatography (HPLC). The HPLAC data reflected the enantioselective retention on a human serum albumin-based chiral stationary phase (HSA-CSP); RP-HPLC data were determined on a specially deactivated hydrocarbon-bonded silica material; NP-HPLC was performed on a graphitized carbon stationary phase. Molecular descriptors reflecting additive-constitutive properties of the solutes as well as their geometry and electron charge distribution were generated using molecular modelling software. The QSRR equations derived for each chromatographic mode involved different sets of molecular descriptors. Analysis of the physical meaning of the individual descriptors allowed for interpretation of separation mechanisms at molecular (submolecular) level and rationalization of the observed separation patterns. For HPLAC the contributions by hydrophobic, steric and electrostatic factors were quantified and accounted for the differential retention of enantiomers. Retention in RP-HPLC was demonstrated to be a net effect of both non-specific (dispersive) and directional (electrostatic) intermolecular interactions between solute and molecules of both stationary and mobile phases. QSRR equations derived for NP-HPLC proved the predominance of specific dipolar and charge-transfer attractive interactions. The QSRR-based models obtained appear a reliable and convincing proof for involvement of distinctive mechanisms in different HPLC systems.

A series of alpha,alpha'-bis[3-(N,N-dialkylcarbamoyl)piperidino]-p- xylenes were synthesized and tested for their inhibitory activity on ADP-induced aggregation of human platelets. A parabolic curve was obtained when log 1/C (activity) was plotted against log P (octanol/water partition coefficient). Using this as a model, a new analogue, alpha,alpha'-bis-[3-(N-methyl-N-butylcarbamoyl)piperidino]-p-xylen e (3g), was synthesized with a predicted IC50 of 25 microM. When this compound was subsequently evaluated, the IC50 was 22.1 +/- 5.5 microM, demonstrating the applicability of this model. The amide oxygen of the carbamoyl substituent appeared necessary for activity. Thus, for example, when the amide carbonyl group of 3a (IC50 = 44.5 microM) was reduced to CH2, the resulting compound 4 had a dramatically reduced activity, IC50 = 1565 microM. Compound 3a was resolved into (+) and (-) enantiomers and a meso (0) diastereomer using fractional crystallization, diastereomeric tartrate formation, and chiral HPLC. Compared to (-)-3a, the (+) isomer was 15 times more potent when ADP was the agonist and 19 times more active when collagen was used as the agonist. Molecular modeling of R,R- and S,S-3a using the SYBYL program was used to examine their interactions with phosphatidylinositol (PI). There was a better fit between PI and the R,R-3a with the energy of interaction being 17.6 kcal/mol less than that of the S,S-3a/PI complex. Although the absolute stereochemistry of individual enantiomers is not known, this study shows that R,R-3a interacts more favorably with PI than does S,S-3a and that (+)-3a is a more potent inhibitor of human platelet aggregation than (-)-3a. It is postulated that because of their lipophilicity, these compounds penetrate the platelet membrane and are then protonated at the pH of the cytosol. The protonated N then neutralizes the anionic charge on the membrane phosphoinositides, thereby rendering them less susceptible to hydrolysis by phospholipase C. Thus, the determinant parameters for optimum antiplatelet activity in 3-carbamoylpiperidines are (1) the amide carbonyl, (2) appropriate stereochemistry of the 3-substituent and (3) a log P value of about 4.5.

Electric dipole moments of nine N, N-dimethylaniline derivatives were determined experimentally in benzene solution according to literature methods. The theoretical dipole moments of these compounds were calculated from molecular orbital approximations according to the Del Re σ-electron treatment, the Huckel π-electron method, the Pariser-Parr-Pople treatment, the complete neglect of differential overlap method, and selected combinations of these methods. Parameters not previously reported were determined for the nitro group by reproduction of experimental dipole moments for use in the Del Re calculations. Comparisons between the experimental and theoretical moments indicate that the combination of the Del Re σ-electron and Huckel π-electron methods gave the best reproduction of the experimental dipole moment values while being considerably less expensive in terms of computer size and time, as well as requiring less time in preparing the data than more sophisticated methods examined.

The Hammett σ and Taft σ0 constants have been examined using the MNDO computational procedure. They are both best explained by using computed properties based upon the benzoate ion, especially the reciprocal of the energy of the highest occupied molecular orbital.

Molecular-orbital calculations have been performed on sydnone, sydnone imine, ψ-oxatriazole, and isosydnone rings and their positive ionized forms by the Pariser–Parr–Pople–Brown–Heffernan method. The importance of elaborate open-shell calculations and the effect of introducing nonneighbor core resonance integrals in this order of approximation are investigated. The available experimental data on closely related compounds are qualitatively in agreement with the calculated values. The computed charges and bond orders demonstrate that certain structural features are common to all five-membered mesoionic ring systems and in agreement with recent experimental findings. On a employe la methode de Pariser–Parr–Pople–Brown–Heffernan, pour calculer les orbitales moleculaires des anneausc de sydnone, de sydnone imine, de ψ-oxatriazole, et d'isosydnone et leurs formes ionisees positives. On a examine l'importance de faire des calculs de “couches ouvertes” et l'effet des integrales de resonance de coeur pour des centres non voisins, dans cette ordre d'approximation. Les donnees experimentales accessibles sur des composes semblables sont en accord qualitatif avec les valeurs calculees. Les indices de charge et de liaison, qui ont ete calcules, montrent qu'il y a des traits structuraux communs a tous les systemes mesoioniques a cinq membres, ce qui est en accord avec des donnees experimentales recentes. Pariser–Parr–Pople–Brown–Heffernan–Berechnungen wurden fur die Molekulorbitale der Ringe des Sydnons, des Sydnonimins, des ψ-Oxatriazols, und des Iso-Sydnons und deren positiven Ionen ausgefuhrt. Es wurde die Bedeutung “offener Schale”-Berechnungen und der Effekt der nichtbenachbarten Resonanzintegrale in dieser Annaherung untersucht. Die vorhandenseienden experimentellen Tatsachen fur verwandten Verbindungen stimmen mit den berechneten Werten qualitativ uberein. Die berechneten Ladungs- und Bindungs-ordnungen zeigen, dass gewisse Strukturzuge fur alle mesoionischen Ringsysteme mit funf Glieder gemeinsam sind, was mit neuen experimentellen Resultaten ubereinstimmt.

The Variable Electronegativity Pariser–Parr–Pople method has been successfully applied to calculate the potential energy curve for the formation of a 1: 1 complex between quinone and hydroquinone. A consistent evaluation of core and electronic repulsion integrals is important to obtain a meaningful curve. A computationally simple procedure has been suggested for separating interactions due to electron exchange between the components from other intermolecular interactions. In agreement with experimental deductions the preferred configuration for the quinone-hydroquinone complex is found to be one in which the molecules are in parallel planes with their C—O bonds parallel. The equilibrium separation between the molecular planes is found to be 2.3 A and the stabilization energy in this position is 1.2 eV. In this equilibrium position forces due to electron exchange constitute the major contributing factor to the stability of the complex.

I N VIEW of the growing interest in the possibility of correlating Hiickel Molecular Orbital (HMO) calculations (38) with biochemical and biological activities (72, 75, 79, 941, and the application of quantum chemistry to drug design (89) , the authors have calculated electron charge distributions of selected cholinesterase inhibitors (80) and are in the process of applying quantum chemistry to our search for effective antimalarials. Two restrictions became apparent a t the onset of these calculations: Parameters were assigned to a limited number of heteroatoms only, and the choice of parameters for a specific heteroatom was dependent upon the method of derivation. With this in mind, the authors decided that a useful contribution to the field would be the publication of a table of the currently available semiempirical parameters and their corresponding derivations and applications, so that other workers would not find it necessary to duplicate this relatively tedious search for the “right” parameter.

The dielectric constants and losses have been measured at 20°C. and wavelengths of 1.25, 3.22, 10.0, 25, and 50 cm., and 575 m. for a series of dilute benzene solutions of a polyester of 1,2-propylene glycol and adipic acid with molecular weight between 5,000 and 7,000. The dielectric constant and loss values are plotted against the weight concentrations of the solute and the slopes of the straight lines thus obtained are examined by four different methods of analysis. The data may be represented in terms of two parameters, a most probable relaxation time and a distribution factor, two relaxation times, or a distribution of relaxation times between two limiting values. The values obtained for the relaxation times are close to those previously found for long-chain fatty acid esters and correspond to relaxation by twisting of short segments containing carboxy groups around bonds in the chain. A value 1.57 × 10—18 obtained for the effective dipole moment of the COOC group as compared to 1.9 × 10—18 in a small monoester indicates some restriction of rotation around the bonds because of mutual repulsion between the polar groups.

Partition coefficients of a series of 2-substituted 3-( N,N -dimethyl)carbamyloxypyridines were determined in an octanol-buffer (pH 7.4) system. The values obtained were compared with the inhibitory potencies of acetylcholinesterase and butyryl-cholinesterase. No significant difference was found for the role of hydrophobicity in the two enzyme systems.

A regression analysis is applied to the hypoglycemic activity data for a series of 12 piperidinesulfamylsemicarbazides. The results are used to estimate the hypoglycemic activity for 12 untested analogs. The following seven untested compounds are predicted to have greater hypoglycemic activity than chlorpropamide: 1, 1-pentamethylene -4- (4-ethyl -4- methyl -1- piperidinesulfamyl) semicarbazide; 1, 1-pentamethylene-4- (4-methoxy-4-methyl-1-piperidinesulfamyl) semicarbazide; 1, 1-pentamethylene-4-(4, 4-diethyl -1- piperidinesulfamyl) semicarbazide; 1, 1- penta-methylene-4-(4-ethyl-4-methoxy -1- piperidinesulfamyl) semicarbazide; 1, 1-penta-methylene-4-(4, 4-dimethoxy -1-piperidinesulfamyl) semicarbazide; 1, 1-hexamethylene-4-(4-methoxy-4-methyl-1-piperidinesulfamyl) semicarbazide; 1, 1-hexamethylene-4-(4-ethyl-4-methoxy-1-piperidinesulfamyl) semicarbazide.

Die Carbonsaure (I) ergibt durch Veresterung, Ammonolyse und Cyclisierung die im Titel genannte Verbindung (II).

Beginnings in quantitative structure-activity relationship (QSAR) studies were made about twenty years ago (Bruice et al., 1956) but only in the last ten years (Hansch and Fujita, 1964; Free and Wilson, 1964) has this powerful methodology been widely applied. The realization that long waiting periods necessary for pharmacological and clinical testing along with the tremendous costs associated with synthesis have “forced” the discovery of techniques that would increase the probability of selecting useful compounds for synthesis and evaluation. When one considers that it costs about $2,000 per compound for synthesis and about $10,000,000 and 10 years to bring a new drug to the market, one must search for more effective ways to select molecules for synthesis and evaluation. QSAR techniques, while not a panacea, are now being used successfully to reach target molecules faster and at less expense. Those using QSAR thoughtfully recognize them as another tool in our background of knowledge much the way an organic chemist uses the tools of infrared and nmr in addition to elemental analysis in compound identification. QSAR should not replace existing experiences in drug design, but it should be added to them (Purcell, 1973).

In 1965 a model to account for the antimalarial activity of chloroquine and its congeners was proposed by O’Brien and Hahn (O’Brien and Hahn, 1965) (see Fig. 1).

Publisher Summary This chapter elaborates the importance of physicochemical parameters in drug design. The studies on drug design show an increase in the use of quantitative structure–activity relationships. Another area of interest in drug design that is growing rapidly is the use of molecular orbital theory in the direct correlation of electronic structure with biological response. When partition coefficients are to be used to correlate molecular structure with biological activity, it is desirable for the properties of the partitioning phases to be as similar to the biological partitioning system as possible. A theoretical analysis of the penetration of drug molecules to their sites of action based upon a model, which treats the membrane or macromolecule as a single phase of lipid character and ignores the nature of its structure, is reported. The bacteriostatic activity of a series of meta- and para-substituted N1-phenylsulfanilamides on E. coli correlated well with modified Hammett substituent constants. There was no significant dependence of activity upon the relative lipophilicity of the compounds studied. The substituent constants for a series of substituted acetophenones based on several different molecular parameters are also calculated.

The purpose of the research is to eradicate chemotherapeutically malarias in the human host; drug resistant strains of P. falciparum constitute the primary target. Our aim is to suggest molecules for synthesis and testing which have a high probability of success as effective antimalarials. This study consists of Free-Wilson and Hansch analyses on a series of compounds to arrive at a consistent model describing the mechanism of interaction. The second major activity consists of molecular orbital calculations of molecules of interest as know or potential antimalarials. Studies in quantitative structure-activity relationships have also been undertaken to bring software to a higher level of sophistication. The decoding of the structure/sub-structure searching programs provided by Walter Reed has been accomplished during this report period. These programs have successfully been translated into language acceptable by the IBM 360/40 system.

Seeking to attain the ultimate goal of rational drug design and to aid in the postulation of drug-action mechani sms at the molecular level , investigators have emp loyed two distinctly different techniques of particular interest to us. in the first techni que, statistical methods have been applied to the corre lati on of biological activity data with either the arbitrary parameters of the mathematical mode ls such as that reported by Free and Wilson [1] or linear free-energy-re lated physi cochemical properties ascribed to portions of the molecule, such as the wide lyapplied model of Hansch [2,3,4]. Although gradual changes in chemical structure and correspond ing changes in biological activity have intrigued sci ent ists for about 100 years [5], signifi cant progress in quantitative correlation techniques has developed only in the past fifteen years or so [6,7,8].