EXPERIENTIA SUPPLE MENTUM 23 Quantitative Structure-Activity Relationships Proceedings of the Conference on Chemical Structure-Biological Activity Relationships: Quantitative Approaches Prague, Czechoslovakia 27 to 29 June, 1973 Editor: Milon Tichy Institute of Hygiene and Epidemiology, Prague Springer Basel AG 1976 Organizing Committee of the Conference: Chairman: A. David Secretary-General: M. Tichy Committee members: K. Boöek J. Kopecky R. Zahradnfk © Springer Basel AG 1976 Ursprünglich erschienen bei Birkhäuser Basel and Stuttgart Softcover reprint of the hardcover 1st edition 1976 ISBN 978-3-0348-5796-3 ISBN 978-3-0348-5795-6 (eBook) DOI 10.1007/978-3-0348-5795-6 CONTENTS Preface 9 1. MA THEMA TICAL EMPIRICAL MODELS OF FREE-WILSON TYPE, FOUR-PARAMETER EQUATION AND RELATED TOPICS, HANSCH APPROACH June C. Joyner and W. P. Purcell Quantum pharmacology and quantitative structure-activity relationships: a brief review 13 R. Franke On the parabolic relationship between biological activity and hydrophobi- city of drugs: transport or protein binding? 25 M. E. Wolff, C. Hansch, P. Kollman, D. G. Giannini and W. L. Duax Quantitation of chemical and biological effects in steroids by Hansch- type and molecular orbital calculations 31 J. C. Dearden, J. H. Collett and E. Tomlinson In vi t ro dissolution rate as a parameter in structure-activity studies 37 C. E. Berkoff, R. D. Cramer III and G. Redl Substructural analysis in drug design 41 M. Kuchar, V. Rejholec, B. BrUnova, Z. Roubal and O. N~mei!ek Structure-activity relationships in a series of cinnamic acids in the sta- bilizing action on erythrocyte membrane 45 5 M. Kuchar, V. Rejholec, V. Rabek, B. Brunova and O. Neme~ek Relationship between RM values from paper chromatography and parti- tion coefficients of dissociable compounds 49 GUiseppina Pelizza, G. Lancini, G. Allievi and G. Gallo The influence of lipophilicity on the antibacterial activity of rifamycins 53 E. Druckrey and W. Dittmar Hansch analysis in a series of substances with antifungal activity 59 L. Drobnica, J. Augustin and P. Nemec Lipophilicity of isothiocyanates as a criterion of their antimicrobial spectrum 65 P. J. Goodford and F. E. Norrington The prediction of new biologically active compounds using physicochem- ical properties-activity relations 79 M. Tichy and Marie Krivucova Use of structure-activity relationships to estimate toxicity of inorganic cations 83 ll. STATISTICAL APPROACHES IN FITTING MODELS S. Wold Some comments on possible types of analogy models in the study of re- lations between chemical structure and biological activity 87 m. CORRELATIONS BETWEEN VARIOUS PHYSICO-CHEMICAL PROPERTIES AND BIOLOGICAL ACTIVITIES V. A. Filov Correlation between physico-chemical properties of chemical compounds and indices of their toxic action: use for prediction 99 V. Rejholec, B. KaMe, M. Kuchar, I. Havlfk, I. Janku, V. TrClka, L. Blaha and J. Weichet • Relationships between some biological and physico-chemical properties in a series of derivatives of Trimepranol [1-(2,3, 5-trimethyl-4-acetoxy- phenoxy) -3-isopropylaminopropane-2-ol1 115 6 K. -J. Schaper and J. K. Seydel Structure-activity correlations in a homologous series of 2-substituted isonicotinic acid hydrazides 119 L. H. Grimme and H. L. N. Harris Substituent effects on the algi.cidal activity of phenyl thiolacetates 125 M. Tichy Interaction of foreign compounds with hemiproteins and isolated ferri- protoheme 131 L. Vrbovsky Structure-toxicity relationships 135 G. Naray-Szab6 Interdependence of various types of pharmacological activity in case of some 4H-pyrido(1, 2a)pyrimidine derivatives 143 J. Saranda and P. Sobotka Structural dependence of epileptogenic action of penicillines 145 IV. CORRELATIONS BETWEEN ELECTRONIC INDICES FROM MOLECULAR ORBITAL CALCULATIONS AND BIOLOGICAL ACTIVITIES L. B. Kier Molecular orbital predictions of properties influencing biological phe nomena 151 F. J. Zeelen Chemical structure-biological activity relationships in the phenoxyacetic acid series 161 I. Lukovits, G. Bicz6 and I. Pataki Correlation between pharmacological activity indices and quantum chem- ical indices of some phenylethylamine derivatives 165 H. P. Tipnis and V. M. Kulkarni Correlation between electronic indices from molecular orbital calcu- lations and antiradiation activity of thiazolidines 171 J. Catalan and J. I. Fernandez-Alonso An investigation of the possible relationship between electronic struc- ture and antirheumatic activity in the hydroxybenzoic acids 177 7 C. A. Ponce, A. Devia and J. I. Fernandez-Alonso CNOO/2 study of the conformational properties of tricyclic antidepres- sants 185 P. A. Kollman, W. J. Murray and M. E. Nuss Theoretical studies of thyroid hormone analogs 193 J. R. Sabin A semi-empirical study of the structural effects of ionic defect forma- tion in a model OI.-helical system 199 J. Koller, A. Azman and N. Trinajstic Ab initio molecular orbital studies in quantum biology. Electronic characteristics of indole and benzofuran 205 K. Waisser, M. Celadnlk, J. Sova and K. Palat The application of Hiickel molecular orbital calculations to study of antituberculotic activity of thioamides 211 V. DISCUSSION OF THE MOST SIGNIFICANT CHARACTERISTICS USED IN THE CORRELATIONS IN TERMS OF A THEORETICAL APPROACH R. Zahradnik, P. Hobza and Z. Slanina Calculations of Henry constants and partition coefficients using quan- tum chemical approach 217 K. Bocek Relationships among activity coefficients, partition coefficients and solubilities 231 W. Draber Binding of small molecules to Sephadex G-10 as a model surface. Cor- relations with extrathermodynamic parameters 241 F. Dittrich and K. R. H. Repke Correlations between dipole moments and biological activities of car- diotonic steroids 249 List of Contributors 255 Subject Index 259 8 PREFACE The conference on "Chemical Structure-Biological Activity: Quantitative Approaches" was held in Prague, Czechoslovakia, on June 27-29, 1973. It took place under the auspices of the J .E. PurkynC! Czechoslovak Medical SOciety, the Czechoslovak Chemi cal SOciety, and the International Society of Quantwn Biology (Organizing Commit tee: A. David, Chairman; M. Tichy, Secretary General; K. Bo~ek, J. Kopeck~·, R. Zahradnik). This volume contains the lectures and communications presented at the conference. There has been an ever increasing interest, especially during the last eight years, in the study of the quantitative relationships between the chemical structure of substan ces and their biological activity (QSAR - quantitative structure-activity relationships). One of the reasons for this increasing interest has been the desire to fmd ways of estimating the quantitative characteristics of a given biological activity as well as to shorten time and reduce the costs of research into optimally active compounds. In contrast to qualitative studies seeking the critical biologically active group, the QSAR approach involves the search for that property, or those properties, which determine the magnitude of the biological effect. Methods of physical chemistry and quantum chemistry appear to be suitable for estimating the quantitative characteristics of the biological activity of different compounds. Forecasting the specific activity of a certain substance by means of theoretical methods is still a matter of future devel opment. One of the basic ideas of QSAR studies is to work with a series of chemical compounds thereby enabling the collection and classification of experimental data. This is the first prerequisite for generalization of knowledge. Most papers presented at the conference showed that such an approach may contribute to the understanding of various theoretical problems of pharmacology, toxicology, physiology, biochemistry, etc. On the other hand, the results obtained stimulated interest in a number of hitherto somewhat neglected physico-chemical problems such as the solubility of substances and their distribution into separate phases. 9 The papers presented cover a number of problems which are currently being studied in the field of QSAR investigations. These papers not only show the progress already made but also indicate the direction of future trends. A second conference on the same subject is planned to take place in three years. In his concluding remarks to the conference, Dr. W. P. Purcell (Memphis, Tenn. U.S.A.), spokesman for the committee appointed to summarize the results of the conference (members of the committee: Dr. V.A. Filov, Leningrad, U.S.S.R.,Dr. R. Franke, Berlin, G.D.R., Dr. L. B. Kier, Boston, Mass., U.S.A., Dr. P. A. KollIilan, San Francisco, Calif., U.S.A., Dr. W. P. Purcell, Memphis, Tenn., U.S.A., Dr. J. K. Seydel, Borstel, F.R.G.) drew attention to certain points. Firstly, that QSAR should be considered as one of the tools providing a better understanding of processes taking place in living organisms which may in the long run result in the ability to predict biological activities of pharmacologically important compounds. Secondly, one must be aware not only of the limitations of this approach but also of the limitations of the statistical analysis used and should not therefore attach exaggerated importance to the results obtained. Thirdly, because of their complementary nature, both molecular orbital calculations and phYSico-chemical experiments should be employed. I t is the wish of the Organizing Committee of the conference that their appreciation be expressed to those who made it possible to organize the conference, especially to Prof. F.Janda, Director of the Institute of Hygiene and Epidemiology, Prague, Dr. A. David, Deputy Director of the Centre of Industrial Hygiene and Occupational Diseases of that institute and President of the Society of Occupational Medicine of the J .E. Purkyn~ Czechoslovak Medical Society, to Dr. I. Jank\1, Scientific Secretary of the Pharmacological Society of the J.E. Purkyn~ Czechoslovak Medical SOCiety, to Dr. K. Blaha, Chairman of the Prague branch of the Czechoslovak Chemical Society and Dr. W. P. Purcell, Secretary of the International Society of Quantum Biology. We should also like to express thanks to Prof. J. Teisinger of the Centre of Industrial Hygiene and Occupational Diseases of the Institute of Hygiene and Epidemiology, Prague, who twenty years ago made it possible to commence studies that were later to develop into QSAR studies. For technical help in preparation of the conference and manuscripts I wish to thank Mrs. M. Markova and Mrs. E. Hynkova from the Institute of Hygiene and Epidemi ology and to Mrs. Z. Jizbova from the Conference Centre of the J.E.Purkynt'! Czechoslovak Medical Society for outstanding help in preliminary work. I am indebted to Dr. R. Zahradnik (J. Heyrovsky Institute of Physical ChemiStry and Electrochem istry, Czechoslovak Academy of Sciences, Prague) for his advice and generous help. Milo1'\. Tichy 10