Background:
The persistence of breast cancer as the leading cause of mortality among women, coupled with drug resistance to
tamoxifen, the standard endocrine therapy for the disease, exacts fixated attention. To this effect, molecular hybridisation offers an
attractive route to drugs with improved bioactivity profile.
Objective:
The primary goal of this study was to examine the potentials of 1H-1,2,3-triazole linked quinoline-isatin molecular hybrids as
drug candidates against breast cancer and methicillin-resistant Staphylococcus aureus (MRSA) cells.
Methods:
The quinoline-isatin hybrids were synthesised via click chemistry-mediated molecular hybridisation strategy. Anti-breast
cancer activity was determined in 3-(4,5-dimethylthiazol-z-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using estrogen-responsive
(ER+) MCF-7 and MDA-MB-231 (triple-negative breast cancer -TNBC) cells while antimicrobial efficacy was established via the broth
dilution method. Also, the toxicity profile of potent compounds to non-cancerous cells was determined using human embryonic kidney
cells (HEK293) and human red blood cells (hRBCs). In silico techniques were employed to predict the drug-like properties of potent
compounds and understand their binding modes with estrogen receptor alpha (ERα).
Results:
Compounds 7g-i exhibited the strongest cytotoxicity to MCF-7 cells with IC50 values of 23.54, 23.66, and 32.50 μM,
respectively. Interestingly, compound 7h also emerged as the best drug candidate against MDA-MB-231 and MRSA cells with IC50 =
71.40 μM and MIC80 = 27.34 μM, respectively. Structure-activity relationship analysis revealed that quinoline-2-carbaldehyde and 5,7-
disubstituted isatin moieties confer desirable potency. These compounds showed no significant cytotoxic or haemolytic effects on
HEK293 or hRBCs in vitro at their active concentrations; hence, eliciting their selectivity for cancer cells. In silico studies also presented
the drugability of potent compounds and the likely structural features interacting with amino acid residues at the ligand-binding domain
of ERα.
Conclusion:
These results suggest that the identified 1H-1,2,3-triazole-linked quinoline-isatin hybrids are viable chemotypes that can be
adopted as templates for the development of new anti-breast cancer and anti-MRSA agents.
In silico investigation of lysostaphin-producing novel strains as an enzybiotic against methicillin-resistant Staphylococcus aureus
