Novel 2-Aminobenzothiazole Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents

Abstract

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.

Figure 1

2-Aminobenzothiazole scaffold.

Figure 2

Compound P1.

Figure 3

Chemical structure of OMS1.

Scheme 1. General Scheme of the Proposed Synthesis Reactions

Scheme 2. Synthetic Pathway of Compounds (OMS1–OMS13)

Figure 4

Chemical structure of OMS2.

Figure 5

Chemical structure of OMS3.

Figure 6

Chemical structure of OMS4.

Figure 7

Chemical structure of OMS5.

Figure 8

Chemical structure of OMS6.

Figure 9

Chemical structure of OMS7.

Figure 10

Chemical structure of OMS8.

Figure 11

Chemical structure of OMS9.

Figure 12

Chemical structure of OMS10.

Figure 13

Chemical structure of OMS11.

Figure 14

Chemical structure of OMS12.

Figure 15

Chemical structure of OMS13.

Scheme 3. Synthetic Pathway of Compound P2

Scheme 4. Synthetic Pathway of Compound P3

Scheme 5. Synthetic Pathway of Compound P4

Scheme 6. Synthetic Pathway of Compound OMS14

Scheme 7. Synthetic Pathway of Compound OMS15

Scheme 8. Synthetic Pathway of Compound OMS16

Figure 16

Chemical structure of OMS14.

Figure 17

Chemical structure of OMS15.

Figure 18

Chemical structure of OMS16.

Figure 19

Gedatolisib ligand and PI3Kγ protein: A: gedatolisib ligand (7JWE), cocrystallized; B: the cocrystallized conformation and the docked conformation of the cocrystallized ligand (7JWE); and C: the PI3Kγ protein’s binding site, represented by PDB code 7JWE.

Figure 20

Cell viability of OMS5 against A549, and OMS14 against A549 and MCF-7 cell lines.

Figure 21

(A) A two-dimensional schematic representation of the interaction of the cocrystallized ligand, VL11201. (B) The OMS14 docked within the ATP binding site of PI3Kγ PDB code: 7JWE, resolution = 2.55 Å.

Figure 22

Pharmacokinetic properties for synthesized derivatives.

Figure 23

%Growth vs Log Conc. For compounds (A) OMS5 and (B) OMS14.