Novel Indole-PABA hybrids as dual hDHFR and CA IX/XII breast cancer inhibitors

Abstract

Background: A library of 8 novel indole-PABA hybrids was designed/ synthesized as hDHFR/CA IX XII dual inhibitors for breast cancer therapy.
Aim: the aim of the study was to investigate the synthesized indole-PABA hybrids as potential hDHFR/CA IX XII dual inhibitors for breast cancer therapy.
Materials and Methods: Target compounds were synthesized by Schiff base method, amide coupling and alkaline hydrolysis methods and confirmed their structures by IR and NMR spectral analysis. Most compounds showed favorable drug-like properties, according to in silico ADMET predictions, and most compounds met Lipinski's Rule of Five, DFT calculations provided insights into electronic reactivity of the compounds depending upon substituents. This in vitro MTT activity against breast cancer cell lines (MDA-MB231 and MCF-7) indicated time-dependent antiproliferative activity.
Results: The most potent compound against MDA-MB-231 cells (IC₅₀ = 19.93 µM at 72 h) was compound 3h (5-bromo-3-chloro derivative), which was more active than the reference compound acetazolamide (IC₅₀ = 24.98 µM at 72 h), compound 3f (5-bromo-2-methyl derivative) being most active against MCF-7 cells (IC₅₀ = 28.56 µM at 72 h). These were confirmed by percentages of cells which are being killed, with 3h and 3b showing the highest efficacy against MDA cells.
Conclusion: The results reveal that there are three compounds 3h, 3b, and 3f, which are potential lead candidates for further optimization and mechanistic studies as multi-target anticancer agents.