achievements with fungicides have come about 
by designing molecules that penetrate rapidly. 
Miller et al. (19) have shown that a material 
such as glyodin is taken up rapidly against a 
concentration gradient so spores will contain 
over 21,000 p.p.m. in 2 minutes. The mem- 
branes of the fungus spore apparently are im- 
paired, as shown by the outward movement of 
solutes from the cell and by more rapid uptake 
of chemicals after exposure to silver. A simi- 
lar effect was obtained with symmetrical 
triazines by Burchfield and Storrs (3). 
There is substantial evidence that the mole- 
cule must have a proper balance between 
lipophilic and hydrophilic properties in order 
to achieve satisfactory permeation (26), These 
properties may be affected by use of an alkyl 
chain of 17 carbons, as in heptadecyl imidazo- 
line (34) and substituted tetrahydropyrimidine 
(24), or 8 carbons on ethylene thiourea (27, 28), 
a parachlorophenyl group, as in the nitroso- 
pyrazoles (18), and possibly a trichloromethyl 
group, as in captan (9, 11), 
There may be much more to this process 
than simple lipid solubility, which would per- 
mit the molecule to pass through the lipid 
phase of a cell membrane if the Danelli con- 
cept applies to fungus membranes, It is en- 
tirely possible that breaking of hydrogen 
bonds or van der Waal's forces between lateral 
protein molecules of the membrane may be 
the primary prerequisite to creating a breach 
into the wall of the membrane, and that there 
is sufficient dislocation in the lipid layer 
underneath to create a small pore. It is obvi- 
ous from the studies cited above, as well as 
many others, that the integrity of the mem- 
brane is ruptured and penetration is not a 
simple diffusion process of molecules dis- 
solved in an aqueous or lipid medium. 
There is a confused state of mind as to 
what happens once the molecule reaches the 
cytoplasmic fluid. Many types of molecules 
are either degraded or bound to metabolites 
rather rapidly, but they do enter into reaction 
with a wide assortment of enzyme systems. 
Reaction with sulfhydryl and amino groups 
of enzymes can be demonstrated in vitro or 
in vivo fairly easily, but exactly which bio- 
chemical process is disrupted sufficiently to 
result in death of the spore is not easily de- 
termined, Owens (20) has reviewed several 
aspects of this problem and cites other com- 
43 
mendable reviews. Very suspect among the 
reactions that take place are blocking of the 
normal phosphate metabolism and disruption 
of the Krebs cycle before citrate can be 
formed from acetate by interference of strong 
oxidants with coenzyme A, This mechanism 
has been studied carefully for ferbam and 
thiram where a series of transformations 
seems to occur. However, reaction with the 
thiol group of coenzyme A would seem to be 
involved (23), as it is in captan (21) and 
dichlone (22), The significance of this site of 
reaction has been confused by other observa- 
tions on the inhibition of aconitase necessary 
for metabolism of citrate and blocking of a 
variety of other enzymes necessary for forma- 
tion of pyruvate and other essential constituents 
of the cells (30), 
Several essential chemical mechanisms are 
being exploited in bringing about the destruc- 
tion of these enzymes. Among these are chela- 
tion of essential metallic ions, alkylating re- 
actions, and interference with the electron 
transport system, 
The idea proposed by Zentmyer (35) in 1944 
that fungicides could operate by chelating es- 
sential bivalent cations, such as zinc, has been 
subject to debate. The idea is fundamentally 
sound but is confused considerably by the fact 
that the copper chelate of oxime is more active 
than unchelated oxime. On the surface this ap- 
pears to refute the suggestion, but supple- 
mentary hypotheses have been advanced that 
the 2:1 chelate promotes penetration of copper 
and then dissociates inside the cell to release 
both a copper toxicant chelated 1:1 anda mole- 
cule of oxime ready to chelate trace elements 
inside the cell. Since the chelation constants 
and competition of different metals for chela- 
tion sites will vary with the supply of elec- 
trolytes and cytoplasmic reaction of the cell, 
the final answers have not been obtained. 
A fresh approach to the problem is being 
taken by Gershon, who has synthesized anum- 
ber of mixed chelates with different dissocia- 
tion constants. Not only can the amount of 
dissociation in the cell be controlled, but one 
of the end products will be essentially inertas 
a fungitoxicant, so it is hoped that by study of 
uptake and fungitoxicity of these compounds (6), 
new information can be obtained onthe validity 
of theories proposed to date. Undoubtedly there 
is potential capacity for chelation as proposed 
