September, 1956 ]
M.
R.
DHANDA
et.
al.
111
At the end of five weeks of incubation, almost the entire inoculum from each of
the flasks containing compounds No. 9, 13, 18, 35 and 36 was transferred to fresh
flasks of drug-free synthetic medium, in order to know if some of the bacilli were
still viable, a possibility to be expected only in the event of drug inhibition being
partial. Subcultures were, at the same time, also made from control flasks without
drugs for comparative study. The results observed at the end of a month and a
half of incubation are indicated in Table II.
The efficacy of compounds No. 1, 9, 13 and 18 showing an appreciable inhibi-
tion at 10 mg. per cent dilution, was also tested in varying concentrations vis a vis
INH and PAS; the results obtained are given in Table III.
DISCUSSION
Perusal of Tables I and III indicates only 4'-Butyro-4-aminodiphenyl (Lab.
Ref. No. 13) to be as effective as INH or PAS in dilutions up to 1 : 100,000, whereas
three other compounds (Lab. Ref. Nos. 1, 9 and 18) compare favourably with them
in somewhat lower dilutions (i.e. up to 1 : 40,000). It is apparent that the suitability
of any of these chemotherapeutic agents for clinical application will largely depend
on their concentration levels permissible in the body, without producing toxic
symptoms and that they will have to be rendered water soluble for the purpose, by
introducing hydrophilic groups, even at the risk of possible reduction in activity.
It cannot, however, be ignored that these trials have got to be evaluated at a credit
for the disadvantage of lack of easy diffusion through the medium on account of low
solubility as also for the larger molecular structures of these compounds, as compared
to INH and PAS, which do not allow the production of comparable molar concen-
trations at each W/V dilution.
An anomaly in the results, set out in Table I is also worth consideration. Con-
trary to expectation, the medium in which agar had been incorporated for keeping
the drugs in a uniform suspension did not prove better than the agar-free medium ;
in most of the cases it allowed better growth of Myco. tuberculosis, indicating thereby,
a lower drug activity. The authors consider one or both of the following possibi-
lities to be responsible for this phenomenon:—
(i) Agar, by virtue of increasing the viscosity of the medium, reduces the diffu-
sibility of the drugs.
(ii) The presence of agar provides an alternative surface for drug absorption.
Although protracted trials of the kind presented in Table II do not give any
idea as to the bactericidal nature of the compounds tried, because of the natural
death of a stationary population due to inanition, they do reflect on the degree of
bacteriostasis induced. Only compounds No. 13 and 18 seem to have completely
inhibited the growth of Myco. tuberculosis in 10 mgm. per cent dilution. In-vivo
trials will, however, be conducted with the soluble derivatives of all the 4 compounds
(Nos. 1, 9, 13 and 18).
It has not been possible to establish any correlation between the basicity and
lipophilic nature of compounds and their anti-tuberculous activity, which seems to
depend largely on individual molecular structure.