Antimycobacterial activity of nitrogen heterocycles derivatives: 7-(pyridine-4-yl)-indolizine derivatives. Part VII^8–12

Figures & data

Scheme 1. Synthesis pathway to obtain indolizineyl-pyridinium quaternary salts 6a–l.

Figure 1. The structure of the reported compound 1 having anti-TB activity⁸.

Table 1. Results of antimycobacterial activity of compounds 6 against M. tuberculosis H37Rv grown under aerobic conditions.

Compound	MIC (μM)	IC50 (μM)	IC90 (μM)	Compound	MIC (μM)	IC50 (μM)	IC90 (μM)
6a	14	13	15	6g	50	35	46
6b	>50	39	>50	6h	14	13	14
6c	15	12	14	6i	8	7.2	8.2
6d	15	14	16	6j	>200	>200	>200
6e	>100	>100	>100	6k	>200	200	>200
6f	20	13	19	6l	>200	>200	>200
6g	50	35	46	6m	>100	>100	>100
Rifampicin	0.0065	0.0036	0.0071	Rifampicin	0.0065	0.0036	0.0071

Bold and italic values indicate the best ones from the series.

Figure 2. SAR conclusions (using anti-TB potential) of the current series.

Table 2. Revaluation of antimycobacterial activity of compounds 6a, 6c, 6d, 6h and 6i against M. tuberculosis H37Rv grown under aerobic conditions.

Compound	MIC aerobic condition (μM)	IC50 (μM)	IC90 (μM)	Compound	MIC aerobic condition (μM)	IC50 (μM)	IC90 (μM)
6a	22	12	23	6h	27	15	26
6c	9.5	6.7	9.5	6i	16	9.8	17
6d	14	12	17	Rifampicin	0.0071	0.0043	0.0092

Table 3. The bactericidal activity (MBC) of compounds 6a, 6c, 6d, 6h and 6i.

Compound	MIC (μM)	MBC (μM)	Concentration dependent	Time dependent
6a	14	14	Y	N
6c	15	3.75	Y	N
6d	15	3.75	Y	N
6h	14	14	N	Y
6i	8	8	Y	N

Table 4. Results of antimycobacterial activity of compounds 6a, 6c, 6d, 6h and 6i against M. tuberculosis H37Rv under low oxygen.

	Low oxygen			Normal oxygen
Compound	MIC (μM)	IC50 (μM)	IC90 (μM)	MIC (μM)	IC50 (μM)	IC90 (μM)
6a	15	12	14	100	9.2	42
6c	57	6.5	18	75	8.1	23
6d	41	7.4	17	43	17	27
6h	100	7.9	37	38	16	24
6i	63	1.9	10	140	6.5	28
Rifampicin	0.018	0.0027	0.0067	0.021	0.0057	0.011
Metronidazole	200	30	64	>200	>200	>200

Table 5. MIC, IC₅₀ and IC₉₀ of compounds 6 against M. tuberculosis resistant at different treatments and non-tuberculous mycobacteria.

	INH-R1			INH-R2			RIF-R1			M. avium
Compound	MIC (μM)	IC50 (μM)	IC90 (μM)	MIC (μM)	IC50 (μM)	IC90 (μM)	MIC (μM)	IC50 (μM)	IC90 (μM)	MIC (μM)
6a	33	13	35	19	12	22	14	8.3	13	50
6c	14	6.9	14	16	6.2	19	10	6.5	10	50
6d	28	14	36	30	15	35	22	12	24	200
6h	>50	18	>50	>50	16	43	24	13	26	200
6i	22	13	23	20	9.8	20	15	7.7	15	50
C1	0.022	0.012	0.031	0.013	0.0070	0.016	5.3	1.1	3.8	0.098^3
C2	>200	>200	>200	>200	>200	>200	0.092	0.063	0.094	–
C3	2.9	1.9	3.0	3.5	2.4	4.3	2.7	1.6	2.6	–
	RIF-R2			FQ-R1			M. abscessus
	MIC (μM)	IC50 (μM)	IC90 (μM)	MIC (μM)	IC50 (μM)	IC90 (μM)	MIC (μM)	IC50 (μM)	IC90 (μM)
6a	31	12	29	31	15	32	>200	24	37
6c	13	8.1	12	16	8	16	23	16	21
6d	16	12	14	32	21	32	>200	81	150
6h	>50	15	>50	>50	26	>50	>200	>200	>200
6i	22	12	22	27	11	28	25	14	23
C1	>50	>50	>50	0.024	0.013	0.033	3.6	2.3	3.6
C2	0.31	0.27	0.30	0.16	0.13	0.15	–	–	–
C3	2.9	1.7	3.0	110	49	110	–	–	–

INH: isoniazid-resistant strains; RIF: rifampicin-resistant strains; FQ: fluoroquinolone-resistant strains; C1: rifampicin control; C2: isoniazid control; C3: levofloxacin control.

Bold and italic values indicate the best ones from the series.

Table 6. Results of cytotoxicity evaluation.

Compound	Cytotoxicity IC50 (μM)	IC50 intracell (μM)	IC90 intracell (μM)
6a	2.9	5.2	15
6c	4.1	7	34
6d	3.9	11	>50
6h	3.8	13	43
6i	3.8	10	48
Control compound^a^,^b	0.020^a	0.18^b	0.27^b

^a Staurosporine control.

^b Isoniazid control.

Table 7. Results of plasma protein binding assay for compound 6i.

Compound	Test species	Mean plasma fraction unbound (%)	Mean plasma fraction bound (%)	Recovery
6i	Human	0.35	99.7	48.7
Propanolol	Human	20.7	79.3	93
Warfarin	Human	0.51	99.5	96.7

Table 8. Permeability evaluation of compound 6i.

Compound	Mean A→B Papp^a (10^−6cm/s)	Mean B→A Papp^a (10^−6cm/s)	Efflux ratio^b
6i	0.76	1.3	1.7
Atenolol	0.13	0.37	2.8
Propanolol	12.7	25	2
Talinolol	0.077	3.3	43

^a Papp is the apparent permeability rate coefficient = (dQ/dt)/(C₀A) where dQ/dt is rate of permeation, C₀ is the initial concentration of compound and A is the area of monolayer.

^b Efflux ratio (Re) is P_app (B→A)/P_app (A→B). An Re > 2 indicated a potential substrate for P-glycoprotein or other active transporters.

Table 9. Cytochrome P450 inhibition results.

	IC50 (μM)
Compound	CYP3A4-Midazolam	CYP3A4-Testosterone	CYP2C9	CYP2D6	CYP2C8	CYP2B6	CYP2C19
6i	0.48	0.081	>5	>5	>5	>5	>5
Ketoconazole^a	0.033	0.022	–	–	–	–	–
Sulfaphenazole^a	–	–	0.16	–	–	–	–
Quinidine^a	–	–	–	0.032	–	–	–
Montelukast^a	–	–	–	–	0.14	–	–
Tranylcypromine^a	–	–	–	–	–	–	7.5
Ticlopidine^a	–	–	–	–	–	0.72	–

^a Control compounds.

Table 10. In vitro microsomal stability assay.

Compound	C (μM)	Test species	NADPH-dependent CLint^a (μL/min/mg)	NADPH-dependent T1/2^b (min)	NADPH-free CLint^a (μL/min/mg)	NADPH-free T1/2^b (min)
6i	1	Human	369	6.3	<12.8	>180
Verapamil	1	Human	123	18.7	<12.8	>180
Dextromethorphan	1	Human	24.3	94.9	<12.8	>180

^a Microsomal intrinsic clearance = ln(2)/(T_1/2[microsomal protein]).

^b Half-life = 0.693/−k, where k is the rate constant.

Danac R, Mangalagiu II. Antimycobacterial activity of nitrogen heterocycles derivatives: bipyridine derivatives. Part III. Eur J Med Chem 2014;74:664–70.

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