Cancer stem cells CD133 inhibition and cytotoxicity of certain 3-phenylthiazolo[3,2-a]benzimidazoles: design, direct synthesis, crystal study and in vitro biological evaluation

Figures & data

Figure 1. Judicious design of target 3-phenylthiazolo[3,2-a]benzimidazoles (Series 2) based on cyclisation of disclosed compounds 2-((benimidazol-2-yl)thio)-1-arylethan-1-ones (Series 1).

Scheme 1. Synthesis of target 3-phenylthiazolo[3,2-a]benzimidazoles 4a–d.

Figure 2. An ORTEP diagram of final X-ray structure of compound 4d.

Table 1. Crystallographic data and refinements for compound 4d.

Crystal data
C15H11N3S	V = 2399.62 (14) Å^3
Mr = 265.33	Z = 8
Monoclinic, P21/n	Mo Kα radiation
a = 9.6379 (3) Å	μ = 0.26 mm^−1
b = 22.8517 (8) Å	T = 100 K
c = 10.9316 (4) Å	0.42 × 0.14 × 0.12 mm
β = 94.666 (1)°	F(000) = 1104
Data collection
Bruker APEX-II D8 venture diffractometer	Rint = 0.041
20125 measured reflections	θmax = 27.5°
5502 independent reflections	4463 reflections with I > 2σ(I)
Refinement
R[F^2 > 2σ(F^2)] = 0.041	0 restraints
wR(F^2) = 0.112	H atoms treated by a mixture of independent and constrained refinement
S = 1.04	w = 1/[σ^2(Fo^2) + (0.0579P)^2 + 1.2502P]
where P = (Fo^2 + 2Fc^2)/3
5502 reflections	Δρmax = 0.41 e Å^−3
359 parameters	Δρmin = −0.31 e Å^−3

Table 2. Hydrogen-bond geometry (Å, °) of 4d.

D—H···A	D—H	H···A	D···A	D—H···A
N3A—H1NA···N2A^i	0.91 (3)	2.19 (2)	3.095 (2)	168 (2)
N3B—H1NB···N2B^i	0.93 (2)	2.18 (2)	3.046 (2)	155 (2)

Symmetry codes: (i) x, y, z − 1.

Table 3. In vitro anti-proliferative activity of compounds 4a–d against colon HT-29 and breast MDA-MB-468 cancer cell lines.

				IC50 (μM)^a
Comp.	R1	R2	R3	HT-29	MDA-MB-468
4a	OMe	H	H	21 ± 1.5	24 ± 1.7
4b	OMe	OH	H	10 ± 0.7	13 ± 0.9
4c	OMe	OMe	OMe	29 ± 2.3	24 ± 2.2
4d	H	NH2	H	NA^b	53 ± 4.7
5-Fluorouracil				16 ± 1.6	41 ± 3.8

^a IC₅₀ values are the mean ± SD of three separate experiments.

^b NA: compounds having IC₅₀ value >100 μM.

Table 4. Inhibition (%) of cell surface expression of CD133 on HT-29 cancer cells at 10 μM.

Comp.	Inhibition (%) ± SD^a
Untreated	–
4a	14 ± 1.0
4b	50 ± 4.3
4c	48 ± 3.8
4d	NA^b

^a Values are the mean ± SD of three separate experiments.

^b Compounds having inhibition % <10.