Synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives, as potential bacterial multidrug resistance pump inhibitors

Figures & data

Figure 1 Structure of reserpine, omeprazole, thioquinoline derivatives and new compounds 1a-m.

Scheme 1 Synthesis of compounds 1a-l. Reagents: (i) DMTHF, CH₃COOH, Δ; (ii) BiCl₃ / NaBH₄, EtOH; (iii) CO(OCCl₃)₂, toluene, Δ; (iv) POCl₃, Δ; (v) Method A: NaH, HS-CH₂-CH₂-R₃, dioxane; Method B: K₂CO₃, HS-CH₂-CH₂-R₃, CuI, HOCH₂CH₂OH, 2-propanol; Method C: t-BuONa, HS-CH₂-CH₂-R₃, CuI, neocuproine, toluene; Method D: t-BuOK, HS-CH₂-CH₂-R₃, Pd(PPh₃)₄, n-BuOH (vi) CS₂, NaOH, EtOH; (vii) NaH, Cl-CH₂-CH₂-R₃, DMF; (viii) HCl, Et₂O.

Table I.  Optimized reaction conditions for coupling of 6a and N,N-diethylaminoethylthiol.

Method	Base	Catalyst	Ligand	Reaction conditions	% Yield of 7a
A	NaH	–	–	dioxane, 100°C, 4 h	42
B	K2CO3	CuI	HOCH2CH2OH	2-propanol, 80°C, 24 h	60
C	t-BuONa	CuI	Neocuproine	toluene, reflux, 24 h	80
D	t-BuOK	Pd(PPh3)4	–	n-BuOH, reflux, 5 h	66

Scheme 2 Synthesis of compound 1m. Reagents: (i) Method A: NaH, HS-CH₂-CH₂-N(C₂H₅)₂, dioxane; (ii) HCl, Et₂O.

Table II.  EPI activities of reserpine, omeprazole, 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline derivatives 1a-l and pyrrolo[1,2-a]thieno[3,2-e]pyrazine 1m on the S. aureus strains, SA 1199B and SA-1.

		SA 1199B			SA-1
		% inhibition^b		MIC(μg/mL)^c	% inhibition^b		MIC(μg/mL)^c
EPI	Concentration^a (μg/mL)	Nor^d	Cip^d	Nor^d	Nor^d	Cip^d	Nor^d
–	–	–	–	64	–	–	16
Reserpine	128	33	69	8	100	100	2
Omeprazole	128	38	69	8	100	100	2
1a	64	28	62	16	79	83	4
1b	64	33	62	8	86	100	2
1c	16	0	15	64	21	17	16
1d	32	28	62	16	71	83	2
1e	4	28	62	16	71	75	2
1f	64	43	77	8	86	92	1
1 g	16	52	85	4	100	100	1
1 h	16	14	38	16	57	67	4
1i	32	14	46	16	50	58	4
1j	16	0	23	32	43	50	8
1k	16	0	31	32	43	50	8
1 l	128	0	23	64	29	25	16
1m	64	48	85	4	100	100	1

^aIn all experiments, the EPIs were used at 0.25 × MIC_(EPI).

^b% inhibition were calculated with the following equation: % = [Ø_R(AB + EPI) - Ø_R(AB)] / [Ø_S(AB) - Ø_R(AB)] × 100 Ø = diameter of the inhibition zone, R = Resistant strain, S = fluoroquinolone susceptible strain, AB = antibiotic, +EPI = in presence of EPI [40].

^cMIC is the minimum inhibitory concentration of norfloxacin in absence or in presence of EPI.

^dNor: norfloxacin, Cip: ciprofloxacin.

Sharma P, Rane N, Pandey P. Synthesis and evaluation of antimicrobial activity of novel hydrazino and N-benzylidinehydrazino-substituted 4,8-dihydro-1H,3H-pyrimido[4,5-d]pyrimidin-2,7-dithiones. Arch Pharm Chem Life Sci 2006; 339: 572–578

 PubMed Web of Science ®Google Scholar