Sixteen novel 2-aminobenzothiazole compounds with different amines or substituted piperazine moieties were designed, synthesized, and tested using various methods. Potential interactions were assessed by docking new compounds in the adenosine triphosphate (ATP) binding domain of the PI3Kγ enzyme (PDB code: 7JWE) by nucleophilic substitution or solvent-free/neat fusion for docked compound synthesis. Final 2-aminobenzothiazole compounds were characterized by direct probe gas chromatography-mass spectrometry (GC-MS), proton (1H-NMR), carbon-13 (13C-NMR), and attenuated total reflectance-infrared Fourier transform infrared (ATR FT-IR). The synthesized compounds were investigated for anticancer activities on lung cancer (A549) and breast cancer (MCF-7) cell lines. The compounds' PI3Kγ inhibition was evaluated at a 100 μM concentration. 4-Nitroaniline and piperazine-4-nitroaniline combination in OMS5 and OMS14 reduced lung and breast cancer cell line growth. IC50 values for OMS5 and OMS14, the strongest compounds, ranged from 22.13 to 61.03 μM. OMS1 and OMS2 inhibited PI3Kγ at the highest rates (47 and 48%, respectively) at a 100 μM concentration. Results show that the PI3Kγ enzyme suppression is not the main mechanism behind these OMS5 and OMS14 anticancer effects. CDK2, Akt, mTOR, and p42/44 MAPK are affected. EGF receptor suppression matters. AKT1, AKT3, CDK1/cyclin B, PDK1 direct, PIK3CA E542 K/PIK3R1 (p110 α/p85 α), PIK3CD/PIK3R1 (p110 δ/p85 α), and PKN inhibition were measured to evaluate the possible mechanism of compound OMS14. PIK3CD/PIK3R1 (p110 δ/p85 α) is the most, with 65% inhibition, suggesting a possible mechanism of anticancer properties. Furthermore, the NCI 60-cell line inhibition demonstrates promising broad anticancer inhibition against numerous cancer cell lines of OMS5 and OMS14, which could be good lead compounds for future development.
© 2024 The Authors. Published by American Chemical Society.