Synthesis and Anti-acute Myeloid Leukemia Activity of Cyclopropane-1,1-diamide Derivatives Containing Imidazo[1,2-a]pyridine

doi:10.6023/cjoc202403053

Abstract

A series of cyclopropane-1,1-diamide derivatives containing imidazo[1,2-a]pyridine were synthesized. The inhibitory effects of these compounds on FLT3-ITD kinase and their anti-proliferative activities against two acute myeloid leukemia cell lines expressing FLT3-ITD were evaluated. With focused on the different substitutions of imidazo[1,2- a]pyridine, a preliminary exploration of the structure-activity relationship was conducted for 22 compounds. The results revealed that most compounds exhibited certain inhibitory effects on FLT3-ITD kinase with IC₅₀ values below 0.5 μmol•L^－1. Among them, N-(4-fluorophenyl)-N-(4-(7-((2-morpholinoethyl)carbamoyl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)cyclo- propane-1,1-dicarboxamide (12a) demonstrated the most potent FLT3-ITD kinase inhibitory activity and the strongest anti-proliferative effect on the MV4-11 and MOLM-13 cell lines expressing FLT3-ITD with IC₅₀ values of 0.06 and 0.2 μmol•L^－1, respectively. Moreover, compound 12a did not exhibit anti-proliferative activity against cell lines without FLT3 muta- tions, such as THP-1, HCT-116, A549, HepG2, K562, and MCF-7, and it displayed non-cytotoxicity towards normal human renal tubular epithelial cells (HK-2), human liver progenitor cells (HepaRG), and HEK293 (human embryonic kidney cells). Although 12a exhibits inferior inhibitory activity against FLT3-ITD kinase and anti-tumor cell proliferation compared to Cabozantinib in this study, it can provide a reference for further research into FLT3-ITD inhibitors.

Key words: imidazole[1,2-a]pyridine, antiproliferative activity, inhibition, FLT3 kinase, acute myeloid leukemia

Cite this article

Lüjia Wu, Jiangdong Li, Zhonghua Shi, Xin Jin, Xianheng Wang, Changkuo Zhao, Qiang Huang. Synthesis and Anti-acute Myeloid Leukemia Activity of Cyclopropane-1,1-diamide Derivatives Containing Imidazo[1,2-a]pyridine[J]. Chinese Journal of Organic Chemistry, 2025, 45(1): 286-296.

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Fig. & Tab. 11

Figure 1. Structures of representative FLT3 inhibitors

Scheme 1. Our previous work and rational design of three novel series of FLT3 inhibitors

Scheme 2. Synthesis of type I series Reagents and conditions: (a) EtOH, 80 ℃, 6 h; (b) 20 mol% I2, DTBP, chlorobenzene, 120 ℃, 12 h; (c) NH3·H2O, 150 ℃, 16 h; (d) 4-fluoroaniline, HATU, DIPEA, DMF, 25 ℃, 4 h; (e) LiOH, MeOH/H2O (V∶V=1∶1), 60 ℃, 2 h; (f) HATU, DIPEA, DMF, 25 ℃, 4 h.

Scheme 3. Synthesis of type II series Reagents and conditions: (a) DMF-DMA, MeOH, reflux, 12 h; (b) 2-bromo-1-(4-nitrophenyl)ethan-1-one, EtOH, reflux, 6 h; (c) H2, Pd/C, EtOH, 40 ℃, 5 h; (d) SOCl2, 60 ℃, 2 h; (e) Et3N, DCM, 6 h.

Scheme 4. Synthesis of type III series Reagents and conditions: (a) chloroacetaldehyde, EtOH, reflux, 12 h; (b) substituted 1-fluoro-4-nitrobenzene, K2CO3, DMF, 80 ℃, 6 h; (c) Pd/C, H2 balloon, MeOH, 25 ℃, 4 h; (d) compound 6, HATU, DIPEA, DMF, 25 ℃, 6 h.

Compd.	IC₅₀/(μmol•L^－1)
Compd.	FLT3-ITD	MV4-11^a	MOLM-13^a
7a	>1.0	>100	>100
7b	>1.0	60.3	93.3
Cabozantinib	0.005	0.003	0.045

Table 1. Structure-activity relationship of compounds 7a and 7b

Figure 2. Docking analysis (PDB ID: 4XUF)

Compd.	IC₅₀/(μmol•L^－1)
Compd.	FLT3-ITD	MV4-11^a	MOLM-13^a
11a	>1.0	5.4	6.2
11b	.0642	0.6	2.0
11c	>1.0	56.1	>100
11d	0.506	4.2	>100
11e	0.369	2.2	1.6
11f	0.232	0.7	0.7
11g	0.246	5.9	0.7
11h	0.228	0.06	2.0
11i	>1.0	9.4	4.2
11j	0.284	37.5	26.1
11k	>1.0	68.51	44.1
11l	>1.0	72	>100
Cabozantinib	0.005	0.006	0.051

Table 2. Structure-activity relationship of compounds 11a~11l

Compd.	IC₅₀/(μmol•L^－1)
Compd.	FLT3-ITD	MV4-11^a	MOLM-13^a
12a	0.127	0.06	0.2
12b	0.322	2.40	8.0
12c	0.0425	0.11	1.3
Cabozantinib	0.005	0.001	0.038

Table 3. Structure-activity relationship of compounds 12a~12c

Compd.	IC₅₀/(μmol•L^－1)
Compd.	FLT3-ITD	MV4-11^a	MOLM-13^a
16a	>1.0	11.36	21.5
16b	>1.0	51.21	50.5
16c	>1.0	41.11	>100
16d	>1.0	78.41	>100
16e	>1.0	>100	>100
Cabozantinib	0.005	0.008	0.041

Table 4. Structure-activity relationship of compounds 16a~16e

Cell line	IC₅₀/(μmol•L^－1)
Cell line	12a	Cabozantinib
MV4-11	0.06	0.003
MOLM-13	0.2	0.045
THP-1	>100	20.3^[19]
HCT-116	>100	15.35^[20]
A549	>100	0.76^[18a]
HepG2	>100	8.48^[21]
K562	>100	2.2^[19]
MCF-7	>100	0.45^[18a]
HEK-293	>100	>100
HepaRG	>100	—
HK-2	>100	1.9

Table 5. Cytotoxicity of 12a on different cell lines

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