Benzothiazole-Triphenylphosphonium Conjugates: Synthesis, In Silico Analysis, and Exploratory In Vitro Effects on...

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Computational Chemistry

Background:

• Colorectal cancer (CRC) remains a significant health challenge.
• Developing novel therapeutic agents for CRC is crucial.
• Triphenylphosphonium (TPP) conjugates offer a promising scaffold for drug development.

Purpose of the Study:

• To synthesize and evaluate novel benzothiazole-triphenylphosphonium (TPP) derivatives for antiproliferative activity against colorectal cancer (CRC) cells.
• To utilize computational methods to guide the design and prioritization of these compounds.
• To investigate the preliminary biological responses of these derivatives in a p53-mutant CRC cell model.

Main Methods:

• Synthesis of benzothiazole-TPP derivatives (4a-f) via acylation and quaternization.
• In silico drug design including QSAR, molecular docking, and molecular dynamics simulations.
• Phenotypic screening using resazurin viability assay in HT-29 CRC cells.
• Gene expression analysis (p21, MDM2 mRNA).

Main Results:

• Compounds 4b and 4c demonstrated concentration-responsive antiproliferative activity with IC50 values of 174 µM and 153 µM, respectively.
• Gene expression analysis indicated upregulation of p21 mRNA with minimal changes in MDM2 mRNA.
• The observed effects in p53-mutant cells are interpreted as stress responses, not direct p53 pathway modulation.

Conclusions:

• An integrated workflow combining synthesis, computational modeling, and biological evaluation was established for novel benzothiazole-TPP derivatives.
• Compounds 4b and 4c represent lead candidates for further optimization in CRC therapy.
• The study provides initial structure-activity relationship insights for this new chemical series.