Synthesis and biological evaluation of novel (E)-N'-benzylidene hydrazides as novel c-Met inhibitors through fragment based virtual screening

Figures & data

Figure 1. Structure of the kinase domain of c-Met bind to GSK1363089, (a) 3D-view image; (b) pose-view image.

Figure 2. (a) Fragment growing based virtual screening; (b) the hit compound docked into c-Met.

Scheme 1. Reagents and conditions: (i) CuSO₄, Vitamin C, EtOH/H₂O, 40 °C, 5–10 h; (ii) NaOH, 6 h, HCl; (iii) hydrazine hydrate, rt, 5 h; (iv) EDCI, HOBt, Et₃N, 35 °C, 8–10 h.

Table 1. Novel compounds and their activities against c-Met.

Compound	R1	R2	R3	R4	R5	IC50(nM)
						c-Met
11a	H	H	H	Cl	H	–^a
11c	H	H	H	OH	H	5681.98
11d	H	OH	H	H	H	–
11e	H	NO2	H	H	H	4276.61
11g	H	OH	Br	H	Br	–
11h	H	OH	H	H	Br	11.93
11j	H	H	OCH3	OCH3	H	3076.1
11k	H	H	OCH3	OCH3	OCH3	–
10a	NHCOCH3	H	H	Cl	H	1.70
10c	NHCOCH3	H	H	OH	H	11184.1
10d	NHCOCH3	OH	H	H	H	266.01
10e	NHCOCH3	NO2	H	H	H	5857.3
10g	NHCOCH3	OH	Br	H	Br	8933.14
10h	NHCOCH3	OH	H	H	Br	–
10i	NHCOCH3	OCH3	H	OCH3	H	1.73
10j	NHCOCH3	H	OCH3	OCH3	H	5.42
10k	NHCOCH3	H	OCH3	OCH3	OCH3	91.52
GSK1363089						0.6

^a –No inhibitory effect.

Table 2. Descriptors and relative importance of descriptors.

Descriptors	Relative importance of descriptors
AM1Eele	0.904317
PM3E	0.500991
AM1E	0.281605
PM3Eele	0.258684
pmiY	0.122461
pmiX	0.071553
pmi3	0.041214
pmi2	0.032288
MNDOE	0.017582
pmi	0.017462

Figure 3. Important structural requirements of (E)-N'-benzylidene hydrazides by means of the ligand based 3D-QSAR.

Table 3. The inhibitory activities of the five compounds against VEGFR-2 and c-Met.

Name	R1	R2	R3	R4	R5	VEGFR-2 (nM)	c-Met (nM)
11b	H	H	Cl	H	H	25.34	3.41
10b	NHCOCH3	H	Cl	H	H	–^a	0.37
11f	H	OH	H	H	Cl	9855.76	–
10f	NHCOCH3	OH	H	H	Cl	139.44	1.19
11i	H	OCH3	H	OCH3	H	849.27	–

^a –No inhibitory effect.

Figure 4. (a) The superposing of c-Met and VEGFR-2 kinase; (b) the active sites of the two kinases; (c) the RMSD value of the superposing conformation.