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 continuous attention.
To this effect, molecular hybridisation offers an attractive route to drugs with improved bioactivity profiles.
Objective: The primary goal of this study was to examine the potential of 1H-1,2,3-triazole linked quinolineisatin
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 druglike
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 32.50μM, respectively. Interestingly, compound 7h also emerged as the best drug candidate against MDAMB-
231 and MRSA cells with IC50=71.40μM and MIC80=27.34μM, 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 ligandbinding
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.