New 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one derivatives as antimicrobial and anti-cancer agents: Synthesis, in-vitro and SAR studies

A new series of biologically active 2,4-diphenyl-N-(4-(thiophen-2-yl)thiazol-2-yl)-3-azabicyclo[3.3.1]nonan-9-imine and N-(4-(naphthalen-2-yl)thiazol-2-yl)-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-imine derivatives 11–18 were synthesized by reaction of the corresponding 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-ones 7–10 with the newly synthesized 2-aminothiazoles 3 and 4. Compounds 7–10 were conveniently synthesized via eco-friendly double Mannich condensation of cyclohexanone (1 equivalent), benzaldehyde derivatives (2 equivalents) and ammonium acetate (1.5 equivalent) in the presence of DMAP (0.5 equivalent). The newly prepared compounds were fully characterized by spectral techniques such as FT-IR, 1H NMR, 13C NMR and elemental analysis. Compounds 11–18 were evaluated in vitro as antimicrobial and anti-cancer agents. Compounds 14 and 17 exerted the highest antimicrobial activity among the other tested compounds, showing the maximum action against Bacillus mycoides (27 and 25 mm, respectively). Additionally, compound 14 showed a minimum inhibition concentration (MIC) value lower than 0.0195 mg/mL against B. mycoides, whereas both compounds (14 and 17) were able to inhibit the growth of Candida albicans at MIC value of 0.0781 mg/ml. Compounds 11, 13 and 18 showed the best cytotoxic activity against A549 cell line (IC50 = 61.20, 57.00 and 17.54 µM, respectively) compared to doxorubicin with IC50 = 52.06 µM. Compounds 11 and 14 showed the best cytotoxic activity against HePG2 cell line (IC50 = 28.97 and 27.69 µM, respectively) compared to doxorubicin with IC50 = 39.74 µM. Expression analysis of liver cancer for compound 14 related to Hexokinase 2 (HK2) and Glutamate-Ammonia Ligase (GLUL) genes was used in HepG2 using RT-qPCR. The negative control of lung and liver cancer cell lines showed a significant increase (p < 0.01) in gene expressions of the CDH1 and IGSF3 compared to the treated cell lines (13, 18 and positive control). Also, the expression of the investigated liver cancer markers in treated (14) and positive control cells was significantly (p < 0.05) lower than their expression in the negative control cells. Gene expression analysis for compound 18 was investigated against lung cancer cell lines using related genes namely, P53, CDK4, BAX, Bcl2 genes. In addition, flow cytometric analysis of apoptosis was studied in 18 treated A549 cell lines.