Table Of ContentEXPERIENTIA 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
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