Design and synthesis of antimicrobial, anticoagulant, and anticholinesterase hybrid molecules from 4-methylumbelliferone

Figures & data

Scheme 1. Synthetic route of dipolarophiles 2 and 3.

Scheme 2. Synthetic route of triazoles 4.

Scheme 3. Synthetic route of isoxazoles 5a–e and isoxazolines 6a–e.

Scheme 4. Synthetic route of aziridines 7a-e.

Table 1. Antibacterial activity of 4-methylumbelliferone and its synthesized derivatives 2, 3, 4a–e, 5a–e, 6a–e, and 7a–e.

	Inhibition zone diameter (mm)
Products^a	Pseudomonas syringae pv, Syringae	Pseudomonas savatanoi	Agrobacterium tumefasciens
1	-	-	-
2	8	10.5	10
3	11.5	12	11
4a	-	9	-
4b	8	8	-
4c	-	-	-
4d	-	-	-
4e	7.5	-	-
5a	-	-	-
5b	-	-	-
5c	-	-	-
5d	-	-	10
5e	-	-	9
6a	11.5	10.5	-
6b	-	-	10
6c	-	-	8.5
6d	-	10.5	8.5
6e	-	-	8.5
7a	9.5	13	11
7b	10.5	-	11
7c	11	11.5	7.5
7d	8.5	11	7.5
7e	10.5	10	-
Ampicillin	22	18	25
DMSO	-	-	-

^aConcentration used = 1 mg/mL.

- no inhibition zone observed.

Table 2. Antifungal activity of compounds 6a and 6d.

	Inhibition zone diameter (mm)
Products^a	Aspergillus flavus	Aspergillus niger	Penicillium italicum
6a	-	-	9.5
6d	9.5	-	-
FONG	37	32.5	40.5
DMSO	-	-	-

FONG: carbendazime 0.5 mg/mL.

^aConcentration used = 1 mg/mL.

- no inhibition zone observed.

Table 3. Anticoagulant activity of 4-methylumbelliferone 1 and its synthesized derivatives 2, 3, 4a–e, 5a–e, 6a–e, and 7a–e.

Compounds^a	1	2	3	4a	4b	4c	4d	4e	5a	5b	5c	5d
aPTT (s)	41.7	63.9	72.7	55.6	58.6	60.8	56.8	59.7	54.6	59.1	55.2	59.9
Compounds	5e	6a	6b	6c	6d	6e	7a	7b	7c	7d	7e
aPTT (s)	58.3	60.2	63.2	61.2	57.2	63.5	54.9	54.9	61.2	74.3	60.4

^aConcentration used = 1000 μg/mL.

Table 4. Anticoagulant activity of compounds 3 and 7d determined by measuring the activated partial thromboplastin time (s) at different concentrations.

[ ] (μg/mL)	0	250	500	1000
3	31.6	39.2	41.9	72.7
7d	31.6	39.3	42.8	74.3

Table 5. Anticholinesterase activity of 4-methylumbelliferone 1 and most of its synthesized derivatives 2, 3, 4, 5, 6, and 7.

Compounds	IC50 (mg/mL)
1	0.692 ± 0.055
2	0.413 ± 0.021
3	0.327 ± 0.012
4a	0.326 ± 0.010
4b	0.360 ± 0.012
4d	0.334 ± 0.021
5a	0.556 ± 0.010
5b	0.553 ± 0.030
5c	0.634 ± 0.010
5d	0.390 ± 0.012
5e	0.495 ± 0.022
6a	0.338 ± 0.011
6b	0.865 ± 0.015
6d	0.415 ± 0.018
6e	0.183 ± 0.020
7a	0.243 ± 0.023
7b	0.427 ± 0.012
7c	0.151 ± 0.012
7d	0.454 ± 0.015
7e	0.292 ± 0.023
Galanthamine	0.38 × 10^−3 ± 0.002 × 10^−3

^aConcentration used = 1 mg/mL.