Synthesis of 1<i>H</i>-1,2,3-Triazole-Linked Quinoline-Isatin Molecular Hybrids as Anti-Breast Cancer and Anti-Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA) Agents

Author(s):

Paul Awolade, Nosipho Cele, Oluwakemi Ebenezer, Nagaraju Kerru, Lalitha Gummidi, Liang Gu, Gabriella Palma, Mandeep Kaur and Parvesh Singh*   Pages 1228 - 1239 ( 12 )

Abstract:

<p>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. </P><P> 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. </P><P> 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 (ER&#945;). </P><P> 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 ER&#945;. </P><P> 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.</p>

Keywords:

Breast cancer, molecular hybridisation, isatin, quinoline, methicillin-resistant Staphylococcus aureus, in silico.

Affiliation:

School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg 2050, School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg 2050, School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg 2050, School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban

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