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A. Mishra et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1719–1723
Broadly all guanidines prepared during this endeavor can be di-
in compound 12{2,3,2} (entry 57) with IC50 as 38.51 nM for the
3D7 strain. On the other hand compounds 12{2,1,1}, 12{2,2,2}
and 12{2,2,3} (entries 50, 54, and 55) displayed IC50 of 65.87,
71.44 and 66.76 nM, respectively against the K1 strain but the cor-
responding SI of 158.06, 21.88 and 47.91 were not very encourag-
ing for further assessment.
Due to significant antibacterial activity of triclosan these com-
pounds were evaluated for antibacterial activity too. The antibacte-
rial evaluation was performed against Escherichia coli (ATCC 9637),
Pseudomonas aeruginosa (ATCC BAA-427), Staphylococcus auerus
(ATCC 25923), and Klebsiella pneumoniae (ATCC 27736) while anti-
fungal assay was carried out against Candida albicans, Cryptococcus
neoformans, Sporothrix schenckii, Tricjophyton mentagrophytes,
Aspergillus fumigatus, Candida parapsilosis (ATCC-22019). The
results of the bioassay against each species are presented in Table 1.
It was observed that with respect to the antibacterial activity com-
pounds having the guanidine group ortho to the ether linkage dis-
played relatively better effect. Against E. coli, two compounds
5{2,1,2,2} (entry 14) and 5{1,2,1,2} (entry 33) displayed potent ef-
vided into two subsets. Whereas the first subset of 31 compounds
which had the guanidine functionality at ortho-position to the
ether linkage comprise of compounds 5{1–2,1,1–3,1–3} (entries
1–18), 12{1,1–2,1–5} (entries 19–28) and 12{1,3,1–5} (entries
29–31), the second subset of 27 compounds having the guanidine
unit at para-position to the ether linkage include compounds
5{1–2,2,1–3,1–3} (entries 32–49) and 12{2,1–3,1–3} (entries 50–
58). Among the first set, while compounds having 2,5-dichloro or
4-(E)-methyl 2-methylbut-2-enoate in the
A
ring viz.
5{1,1,1–3,1–3} or 12{1,1–3,1–3} displayed promising activity
against the 3D7 strain, compounds 5{2,1,1–3,1–3} having 4-meth-
oxy as substituent were relatively less active. Further it was ob-
served that for compounds carrying 2,5-dichoro or 4-methoxy
group in the A-ring as compared to propyl and butyl spacer in
the diaminoalkyl chain, the presence of ethyl spacer was more
effective for antiplasmodial activity against the 3D7 strain. In
general it was observed that the unsubstituted phenyl as the C-ring
was preferred group for the antiplasmodial activity and the activity
of these compounds ranged between 42 and 69 nM which were at
least 7–10 folds less as compared to the standard CQ. But the best
IC50 of 37.56 nM among these analogues was observed in 5{2,1,2,3}
(entry 15) which had 3-Cl substitution in the C-ring and a butyl
spacer in the diaminoalkyl chain. On the other hand for compounds
having acrylate group in the A-ring, propyl spacer and a 3-chloro
group in the C-ring was observed to be more suited for antiplasmo-
dial efficacy. This was evident from the antiplasmodial efficacy of
20.34–34.87 nM in compounds 12{1,2,1–3} (entries 24–26) though
it was 3–5 fold less than the standard CQ. For activity against the
K1 strain among the compounds from this set we did not observe
any good correlation between the structure and the activity. For
compounds having either 2,5-dichloro or 4-methoxy substitution
in the A-ring, compound 5{1,1,2,2} (entry 5) bearing 3-chloro
group in the C-ring with IC50 of 77.71 nM was the most active
albeit with poor SI. Besides compounds having 2,5-dichloro
substitution on the A-ring and unsubstituted phenyl as the C-ring
viz. 5{1,1,1,1–3} (entries 1–3) displayed antiplasmodial efficacies
which were 2–4 times better as compared to CQ for this strain.
For compounds with acrylate substitution in the A-ring none of
the compound except for 12{1,3,3} (entry 31) with IC50 of
41.24 nM displayed any significant inhibition. Expectedly, replac-
ing the diaminoalkyl quinoline moiety with benzylamine or cyclo-
propyl amine resulted in complete loss of activity (entries 22, 23,
27, and 28).
Compared to the first set, the second set of compounds having
the ether linkage para to the guanidino group elicited relatively
better antiplasmodial effect. Unlike the previous set here the com-
pounds with 2,5-dichloro, 4-methoxy or 4-(E)-methyl 2-methyl-
but-2-enoate groups did not display much distinction of
bioactivity. Two compounds 5{1,2,1,2} (entry 33) and 5{1,2,3,3}
(entry 40) carrying 2,5-dichloro substitution in the A ring were
the most active compounds with IC50 of 23.12 and 29.02 nM,
respectively against the 3D7 strain. The compounds 5{2,2,1,2}
(entry 42) and 5{2,2,3,3} (entry 49) carrying the 4-methoxy substi-
tutions also displayed promising antiplasmodial effect with IC50 of
36.63 and 33.7 nM, respectively. Unfortunately however, these
analogs did not display any significant activity against the K1
strain of P. falciparum. On the other hand compound 5{1,2,3,1} (en-
try 38) which had IC50 of 43.97 nM against the 3D7 strain also
showed good activity (IC50 = 54.06 nM) for the K1 strain with SI
of 188. In general for this set it was observed that compounds with
ethyl spacer in the diaminoalkyl chain were relatively less effective
as compared to corresponding ethyl and butyl analogs. For com-
pounds bearing 4-(E)-methyl 2-methylbut-2-enoate in A-ring all
compounds displayed activity with IC50s ranging between 38.51
and 94.42 nM for the 3D7 strain. The best activity was observed
fect at 3.12 lg/mL though it was twofolds less than the standard
gentamycin used in the assay. It may be noted that these com-
pounds either had dichloro or methoxy substitution in the A ring
but no compound bearing 4-(E)-methyl 2-methylbut-2-enoate in
the A ring displayed promising effect. Although no compound elic-
ited significant effect against P. aeruginosa, several compounds dis-
played pronounced antibacterial activity against S. aureus. Most of
the active compounds herein had the guanidino group ortho to the
ether linkage. All compounds having 3,5-dichloro-substitution in
the A ring and 3-chloro substitution in the C ring irrespective of
the different in carbon spacer in the quinoline ring displayed MIC
of 1.56 lg/mL was equivalent to that of gentamycin (entries
4–6). However changing the substitution from 3-chloro to 4-chloro
in these compounds resulted in loss of activity (entries 7–9). In
contrast the compounds having 4-(E)-methyl 2-methylbut-2-
enoate substitution in the A-ring displayed potent activity only
when the 4-chloro substituted C-ring (entries 29–31) whereas
compounds containing 3-chloro-substititions were less active.
Notably the MIC of 1.56 lg/mL displayed by these compounds
was at least twofolds less as compared to Norfloxacin, one of the
other reference drugs used in the system. Of all the compounds
screened against K. pneumoniae only two compounds 12{1,2,1}
and 12{1,2,2} elicited MIC of 3.12 lg/mL which was two folds infe-
rior to the gentamycin (entries 24 and 25).
Additionally we evaluated these compounds for their antifungal
effect but the results were not very encouraging. Though several
compounds displayed moderate antifungal efficacy against the
six different strains, the activity was several folds less relative to
the reference drugs. Only one compound 12{2,1,1} displayed MIC
of 1.52 lg/mL against C. albicans.
In summary we have disclosed the synthesis, antiplasmodial
and antibacterial activity of new quinoline triple hybrids bearing
certain knowledge-based substructural units (diaryl ether and gua-
nidine) ascribed wh antiinfective activities. Based on the SAR of the
compounds prepared and investigated during the present endea-
vor it is concluded that the quinoline-hybrids with the following
attributes are preferred to display significant antiplasmodial
activity; (a) presence of guanidine unit at the para-position of
the B phenyl ring, (b) a 3-chloro-substitution on the C phenyl ring,
(c) a 4-(E)-methyl 2-methylbut-2-enoate group on the A phenyl
ring and (d) a propyl spacer between the nitrogen at the 4-position
of the quinoline ring and the nitrogen of the guanidine unit. On the
other hand the antibacterial activity was found to be concentrated
in compounds bearing 4-(E)-methyl 2-methylbut-2-enoate group
derived from the MBH chemistry as compared to simple chloro
or methoxy substituted phenyl ring. Further study to access a rel-
atively better antiplasmodial agent using quinoline-hybrid concept
Mishra, Amita
