In the era of data science, data-driven algorithms have emerged as powerful platforms that can consolidate bioisosteric rules for preferential modifications on small molecules with a common molecular scaffold. Here we present complementary data-driven algorithms to minimize the search in chemical space for phenylthiazole-containing molecules that bind the RNA hairpin within the ribosomal peptidyl transferase center (PTC) of Mycobacterium tuberculosis. Our results indicate visual, geometrical, and chemical features that enhance the binding to the targeted RNA. Functional validation was conducted after synthesizing 10 small molecules pinpointed computationally. Four of the 10 were found to be potent inhibitors that target hairpin 91 in the ribosomal PTC of M. tuberculosis and, as a result, stop translation.
Graphical Abstract
A series of novel
4-aminoquinoline analogues bearing a methyl group
at 4-aminoquinoline moiety were synthesized via a
new and robust synthetic route comprising in situ
tert-butoxycarbonyl (Boc) deprotection–methylation
cascade resulting in the corresponding N-methylated secondary amine
using Red-Al and an efficient microwave-assisted strategy for the
fusion of N-methylated secondary amine with 4-chloroquinoline nucleus
to access the series of novel 4-N-methylaminoquinoline
analogues. The new series of compounds were evaluated for their antimalarial
activity in in vitro and in vivo models. Among 21 tested compounds, 9a–i have shown a half-maximal inhibitory concentration (IC50) value less than 0.5 μM (i.e., <500
nM) against both chloroquine-sensitive strain 3D7 and chloroquine-resistant
strain K1 of Plasmodium falciparum with
acceptable cytotoxicity. Based on the in vitro antimalarial
activity, selected compounds were screened for their in vivo antimalarial activity against Plasmodium yoelii nigeriensis (a multidrug-resistant) parasite in Swiss mice. Most of the compounds
have shown significant inhibition on day 4 post infection at the oral
dose of 100 mg/kg. Compound 9a has shown 100% parasite
inhibition on day 4, and out of five treated mice, two were cured
till the end of the experiment. The present study suggests that 4-methylamino
substitution is well tolerated for the antiplasmodial activity with
reduced toxicity and therefore will be highly useful for the discovery
of a new antimalarial agent against drug-resistant malaria.
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