Synthesis and antileishmanial and antimicrobial activities of some 2,3-disubstituted 3H-quinazolin-4-ones

Figures & data

Scheme 1.  General schematic synthesis of 2,3-disubstituted 3H-quinazolin-4-ones. Reagents and conditions: (a) thionyl chloride, DMF, reflux; (b) anthranilic acid, pyridine (dry), stir; (c) primary amine, pyridine/benzene, reflux 2–3 h; (d) triethylorthoacetate, para-toluenesulfonic acid (PTSA), primary amine, stir, r.t.; (e) primary amine, ethanol, reflux 2 h.

Scheme 2.  Mechanism of formation of 2,3-disubstituted 3H-quinazolin-4-ones.

Table 1.  Synthesized 2,3-disubstituted quianzolin-4(3H)-ones 7–19 (see Scheme 2).

Compound	R1	R2
7	4-NO2-C6H4	CH2CH2OH
8	4-Cl-C6H4	NH2
9	C6H5	NH2
10	C6H5	4-I-C6H4
11	C6H5	CH2C6H5
12	C6H5	2,3,4-Trimethylphenyl
13	4-CH3-C6H4	NH2
14	4-NO2-C6H4
15	C6H5	CH2CH2OH
16	C6H5	4-Br-C6H4
17	C6H5	4-CH3-C6H4
18	CH3	4-CH3-C6H4
19	CH3	CH2CH2OH

Table 2.  Antibacterial activities (mm) at 1 mg/mL.

Compound	B. subtilis	S. aureus	E. coli	S. flexneri	P. aeruginosa	S. tyhphi
7	—	—	—	—	—	—
8	—	—	—	—	—	—
9	12	16	15	—	—	23
10	—	—	—	—	—	—
11	—	13	—	—	—	—
12	40	40	44	—	—	46
13	—	—	—	—	—	—
14	—	—	—	—	—	—
15	—	—	—	—	—	—
16	—	—	—	—	—	—
17	—	—	—	—	—	—
18	—	—	—	—	—	—
19	16	20	16	13	—	16
SD	26	17	25	24	17	21

Note. SD (imipenem) = 100 μg/mL; —, inactive.

Table 3.  Antibacterial activities (MIC) of active compounds 9, 11, 12, and 13.

Compound	i		ii		iii		iv		v		vi
	a	b	a	b	a	b	a	b	a	b	a	b
9	12	3.7	16	3.0	15	3.0	—	—	—	—	23	0.29
11	—	—	13	3.7	—	—	—	—	—	—	—	—
12	40	0.15	40	0.15	44	0.13	—	—	—	—	46	0.11
19	16	3.0	20	0.9	16	3.0	13	—	—	—	16	3.0
Imi	26	0.28	17	2.9	25	0.26	24	0.34	17	2.9	21	0.7

Note. i, Bacillus subtilus (ATCC 6633); ii; Staphylococcus aureus (ATCC 25923); iii, Escherichia coli (ATCC 25922); iv, Shigella flexneri (clinical isolate); v, Pseudomonas aeruginosa (ATCC 27853); vi, Salmonella typhi (ATCC 19430); a, zone of inhibition (mm); b, MIC (μg/mL); Imi, imipenem; —, not determined/inactive.

Table 4.  Antifungal activities (% inhibition) at 200 μg/mL.

Compound	T. longifusus	C. albicans	A. flavus	M. canis	F. solani	C. glabrata
7	20	00	00	50	50	00
8	50	18	00	20	30	00
9	00	00	00	00	00	00
10	40	00	00	50	00	00
12	40	00	00	50	00	00
15	00	00	00	00	00	00
16	50	00	00	20	00	00
SD^1,2	70^1	110^1	20^2	98.4^1	73^1	110^1

Note. SD¹, miconazole; SD², amphotericin B.

Table 5.  Antifungal activities (MIC) of compounds 7, 8, 10, 12, and 18.

Compound	i		ii		iii		iv		v		vi
	a	b	a	b	a	b	a	b	a	b	a	b
7	20	5.7	00	—	—	—	50	3.1	50	3.0	—	—
8	50	3.0	18	5.8	—	—	20	5.7	30	5.0	—	—
10	40	3.4	—	—	—	—	50	3.0	—	—	—	—
12	40	3.4	—	—	—	—	50	3.0	—	—	—	—
16	50	3.0	—	—	—	—	20	5.6	—	—	—	—
Mic	70	1.4	29	4.8	ND	ND	98	0.4	73	1.6	99	0.4
Amp	ND	ND	ND	ND	73	1.6	ND	ND	ND	ND	ND	ND

Note. i, Trichophyton longifusus (clinical isolate); ii, Candida albicans (ATCC 2091); iii, Aspergillus flavus (ATCC 32611); iv, Mycosporum canis (ATCC 11622); v, Fusarium solani (ATCC 11712); vi, Candida glabrata (ATCC 90030); a, % inhibition; b, MIC (μg/mL); Mic, miconazole; Amp, amphotericin B; ND, not done.

Table 6.  Leishmanicidal activities (IC₅₀ values) of compounds 7–19.

Compound	IC50 (µg/mL)
7	71.00
8	96.20 (±0.78)
9	—
10	—
11	48.19 (±0.57)
12	98.021 (±0.71)
13	—
14	—
15	71.95
16	—
17	—
18	—
19	95.6 (±1.0)
Amphotericin B	0.50