Development of novel isatin–nicotinohydrazide hybrids with potent activity against susceptible/resistant Mycobacterium tuberculosis and bronchitis causing–bacteria

Figures & data

Figure 1. Structures of some reported isatin-based anti-mycobacterial agents (I–III).

Figure 2. Design of the target hybrids 5a–m, 9a–c, and 14.

Scheme 1. Synthesis of target isatin hybrids 5a–m; (i) NH₂NH₂.H₂O/methanol/reflux 4 h, (ii) R₁-Br/DMF/KI (Cat.)/K₂CO₃/reflux 3 h, (iii) Ethanol absolute/drops glacial acetic acid (Cat.)/reflux 6 h.

Scheme 2. Synthesis of target isatin hybrids 9a–c; (i) ethyl acetoacetate/NH₄OAc/glacial acetic acid/reflux 6 h, (ii) NH₂NH₂.H₂O/methanol/reflux 6 h, (iii) Ethanol absolute/drops glacial acetic acid (Cat.)/reflux 6 h.

Scheme 3. Synthesis of target compound 14; (i) NaOH/MeOH/reflux 6 h, (ii) SOCl₂/reflux 4 h, (iii) NaN₃/acetone/stirring at R.T. 4 h, (iv) Dry toluene/reflux 1 h, (v) Dry toluene/reflux 5 h.

Table 1. MIC (µg/mL) for hybrids (5a–m, 9a–c, and 14) against M. tuberculosis (ATCC 27294) and Isoniazid/Streptomycin resistant M. tuberculosis (ATCC 35823), and LogP measurements for hybrids (5a–m, 9a–c, and 14).

Compound	X or R2	R	R1	M. tuberculosis (ATCC 27294)	M. tuberculosis (ATCC 35823)	LogP
5a	H	–CH2CH2CH3		3.9	125	1.65
5b	H	–CH2CH(CH3)2		1.95	62.5	2.04
5c	H	–CH2COOCH2CH3		7.81	NA	1.46
5d	H	–CH2C6H5		0.24	15.63	2.55
5e	Cl	–CH2CH2CH3		3.9	NA	2.2
5f	Cl	–CH2CH(CH3)2		0.48	15.63	2.6
5g	Br	–CH2CH2CH3		0.24	3.9	2.47
5h	Br	–CH2CH(CH3)2		0.24	3.9	2.87
5i	Br	–CH2COOCH2CH3		7.81	NA	2.29
5j	H	–CH2CH2CH3	OCH3	0.98	15.63	2.24
5k	H	–CH2CH(CH3)2	OCH3	0.98	62.5	2.63
5l	H	–CH2COOCH2CH3	OCH3	3.9	125	2.05
5m	H	–CH2C6H5	OCH3	7.81	NA	3.14
9a	CH3	–CH2CH2CH3	C6H5	31.25	NA	4.45
9b	CH3	–CH2CH(CH3)2	C6H5	15.63	NA	4.85
9c	CH3	–CH2COOCH2CH3	C6H5	15.63	NA	4.26
14				3.9	62.5	1.94
INH				0.24	>125
Streptomycin					>125

NA: not determined, MIC >125 µg/mL.

Bold values represent the best activity.

Figure 3. Summary for the structure activity relationships for anti-mycobacterial activity of the target hybrids.

Table 2. MIC (µg/mL) for hybrids (5a–m, 9a–c, and 14) against bronchitis causing-bacteria as determined using XTT assay.

Compound	M. pneumoniae (ATCC 15531)	H. influenzae (ATCC 10211)	S. pneumoniae (ATCC 1659)	K. pneumoniae (ATCC 43816)	M. catarrhalis (ATCC 25238)	B. pertussis (ATCC 9340)
5a	7.81	7.81	1.95	0.49	31.25	3.9
5b	1.95	0.98	1.95	0.49	7.81	1.95
5c	31.25	7.81	3.9	1.95	NA	7.81
5d	3.9	0.98	1.95	0.49	7.81	1.95
5e	7.81	7.81	1.95	0.98	15.63	7.81
5f	3.9	1.95	1.95	0.49	3.9	1.95
5g	1.95	0.98	1.95	0.24	3.9	1.95
5h	1.95	0.98	1.95	0.49	3.9	1.95
5i	15.63	7.81	1.95	0.98	NA	7.81
5j	3.9	3.9	1.95	0.49	7.81	3.9
5k	0.98	0.98	1.95	0.49	3.9	1.95
5l	7.81	15.63	1.95	0.98	15.63	15.63
5m	62.5	7.81	7.81	1.95	NA	7.81
9a	125	31.25	7.81	7.81	NA	15.63
9b	125	62.5	15.63	7.81	NA	31.25
9c	125	15.63	15.63	3.9	NA	7.81
14	3.9	1.95	1.95	0.49	15.63	1.95
Azith.	1.95	3.9	0.98	0.49	7.81	3.9

NA: not determined.

Bold values represent the best activity.

Table 3. In vitro cytotoxic effect for hybrids 5g and 5h towards non-tumorigenic WI-38 cells, and their Selectivity index (S.I.).

Compound	IC50 WI-38 cells (µg/mL)	MIC Resistant TB (µg/mL)	Selectivity Index
5g	60.95 ± 3.17	3.9	15.6
5h	54.01 ± 2.69	3.9	13.8

Figure 4. The 2D diagram and 3D representation for compound 5g displaying its interactions with the DprE1 binding site.

Figure 5. The 2D diagram and 3D representation for compound 5h displaying its interactions with the DprE1 binding site.