Design, synthesis and antifungal activity of threoninamide carbamate derivatives via pharmacophore model

Figures & data

Figure 1. The pharmacophore model of three active fragments.

Figure 2. The three structures of designed threonine derivatives.

Scheme 1. The synthetic route of threonine derivatives.

Scheme 2. The general synthesis procedure of intermediate amine.

Table 1. The EC₅₀ values of threonine derivatives against P. capsici.

No.	Substituents			y = a + bx	r^2	EC50 μg/mL
	R^1	R^2	R^3
I-1	H	Bn	Me	y = 4.3155 + 2.1632x	0.9428	2.07 ± 0.23
I-2	p-F	Bn	Me	y = 3.9699 + 2.1549x	0.9732	3.01 ± 0.26
I-3	m-F	Bn	Me	y = 4.6558 + 2.4035x	0.9324	1.39 ± 0.12
I-4	o-F	Bn	Me	y = 3.3251 + 1.9884x	0.9712	7.27 ± 0.55
I-5	p-Cl	Bn	Me	y = 3.6066 + 5.0563x	0.8993	1.24 ± 0.09
I-6	p-Me	Bn	Me	y = 4.9478 + 4.3944x	0.9642	2.05 ± 0.24
I-7	p-MeO	Bn	Me	y = 5.2613 + 2.7141x	0.9842	0.80 ± 0.05
I-8	m-MeO	Bn	Me	y = 3.1218 + 2.3592x	0.9701	6.26 ± 0.67
I-9	o-MeO	Bn	Me	y = 4.2385 + 1.9024x	0.9971	4.98 ± 0.88
I-10	p-Pgoxy	Bn	Me	y = 5.8080 + 2.4155x	0.9666	0.46 ± 0.03
I-11	3,4-diMeO	Bn	Me	y = 5.3971 + 1.5023x	0.6145	0.56 ± 0.03
I-12	3-MeO-4-Pgoxy	Bn	Me	y = 5.2252 + 1.5371x	0.9365	0.27 ± 0.16
I-13	3,4-diMeO	Bn	Ph	y = 3.6127 + 0.8547x	0.9941	42.06 ± 10.83
I-14	3,4-diMeO	Bn	p-FPh	y = 2.5553 + 1.5583x	0.9967	37.05 ± 5.44
I-15	3,4-diMeO	Bn	p-ClPh	y = 3.3650 + 1.0454x	0.9537	36.63 ± 7.32
I-16	3,4-diMeO	Bn	p-BrPh	y = 2.9715 + 1.4550x	0.9909	24.78 ± 2.99
I-17	3,4-diMeO	Bn	p-MePh	y = 0.2597 + 5.6567x	0.9286	8.88 ± 1.32
I-18	p-F	3,4-diMeOBn	Me	y = 4.3397 + 1.8195x	0.9477	2.31 ± 0.19
I-19	p-Me	3,4-diMeOBn	Me	y = 2.8108 + 4.2031x	0.9186	3.49 ± 0.55
I-20	p-Pgoxy	3,4-diMeOBn	Me	y = 4.3534 + 1.4515x	0.9868	2.80 ± 0.32
I-21	p-MeO	3,4-diMeOBn	Me	y = 4.0306 + 1.4599x	0.9478	4.63 ± 0.68
I-22	p-Me	p-FBn	Me	y = 6.0925 + 3.2941x	0.9436	0.48 ± 0.03
I-23	p-MeO	p-FBn	Me	y = 5.9086 + 2.9268x	0.9855	0.49 ± 0.03
I-24	p-Pgoxy	p-FBn	Me	y = 6.5167 + 1.6990x	0.7882	0.14 ± 0.02
I-25	3,4-diMeO	p-FBn	Me	y = 5.9157 + 7.1783x	0.9198	0.81 ± 0.03
I-26	3-MeO-4-Pgoxy	p-FBn	Me	y = 5.2526 + 2.3695x	0.9404	0.85 ± 0.05
I-27	3-MeO-4-Pgoxy	p-ClBn	Me	y = 4.5461 + 0.9908x	0.9826	2.64 ± 0.32
I-28	p-MeO	p-ClBn	Me	y = 4.1546 + 0.9741x	0.9975	7.93 ± 2.37
I-29	p-Pgoxy	p-ClBn	Me	y = 4.2866 + 0.8404x	0.9841	6.99 ± 1.30
I-30	p-MeO	p-MeOBn	Me	y = 4.6371 + 1.8188x	0.9913	1.59 ± 0.12
I-31	p-Pgoxy	p-MeOBn	Me	y = 4.8542 + 2.4195x	0.9967	1.26 ± 0.08
I-32	3-MeO-4-Pgoxy	p-MeOBn	Me	y = 3.9844 + 2.3635x	0.9867	1.77 ± 0.06
I-33	p-MeO	p-MeBn	Me	y = 3.9560 + 1.2618x	0.9974	6.72 ± 0.88
I-34	p-Pgoxy	p-MeBn	Me	y = 3.6684 + 1.4766x	0.9842	9.29 ± 1.06
I-35	3,4-diMeO	p-MeBn	Me	y = 1.7805 + 6.9131x	0.9695	3.10 ± 0.23
I-36	3-MeO-4-Pgoxy	p-MeBn	Me	y = 4.2233 + 1.7183x	0.9910	1.23 ± 0.30
dimethomorph				y = 6.5558 + 1.6550x	0.9930	0.37 ± 0.03

Table 2. The in vivo fungicidal activity against two fungi of some compounds.

No.	P. capsici (%, μg/mL)					P. cubensis (%, μg/mL)
	50	25	12.5	6.25	3.125	50	25	12.5	6.25
I-1	100 ± 0	100 ± 0	47.8 ± 2.3	42.6 ± 1.6	30.4 ± 1.5	83.4 ± 1.5	63.5 ± 3.2	47.0 ± 2.3	40.3 ± 2.4
I-2	87.2 ± 1.3	53.2 ± 1.4	40.4 ± 1.6	36.2 ± 3.1	14.9 ± 2.1	96.7 ± 0.8	90.1 ± 1.5	73.5 ± 5.2	66.9 ± 3.3
I-3	100 ± 0	83.0 ± 0.9	66.0 ± 2.8	27.7 ± 2.5	14.9 ± 3.3	86.7 ± 3.2	66.9 ± 4.2	60.2 ± 4.4	60.2 ± 5.1
I-6	100 ± 0	61.7 ± 2.5	40.4 ± 3.4	66.0 ± 3.1	48.9 ± 5.2	90.1 ± 1.1	73.5 ± 3.3	66.9 ± 3.1	53.6 ± 2.1
I-7	83.0 ± 1.9	78.7 ± 3.6	74.5 ± 2.3	53.2 ± 1.6	nt	76.8 ± 4.2	66.9 ± 2.1	53.6 ± 6.8	47.0 ± 5.2
I-10	65.2 ± 4.6	65.2 ± 1.3	52.2 ± 3.9	30.4 ± 2.1	nt	73.9 ± 6.5	63.8 ± 1.5	52.7 ± 7.2	36.0 ± 1.8
I-18	69.6 ± 2.1	65.2 ± 0.5	30.4 ± 2.2	nt	nt	66.9 ± 2.2	58.2 ± 2.6	47.1 ± 2.5	39.7 ± 9.4
I-23	83.6 ± 3.2	68.2 ± 2.2	63.6 ± 1.5	45.5 ± 1.8	0	76.4 ± 1.3	62.8 ± 4.2	69.0 ± 4.2	55.0 ± 2.3
dimethomorph	100 ± 0	100 ± 0	100 ± 0	87.0 ± 2.1	62.5 ± 1.2	74.2 ± 2.5	69.0 ± 2.1	61.3 ± 2.5	46.9 ± 4.1

Table 3. The in vitro fungicidal activity of compound at 50 μg/mL.

No.	FO	CA	PP	AS	GZ	PI	SS	BC	RS
I-1	18.2 ± 1.9	36.8 ± 2.2	81.4 ± 2.1	72.4 ± 1.6	nt	52.5 ± 2.6	87.0 ± 2.2	69.2 ± 2.5	90.8 ± 2.2
I-2	45.0 ± 2.1	45.5 ± 3.2	90.5 ± 0.9	62.5 ± 0.8	36.4 ± 1.6	53.3 ± 2.4	86.4 ± 1.6	66.7 ± 1.5	76.3 ± 3.1
I-3	13.6 ± 1.2	26.3 ± 1.7	43.0 ± 3.2	79.3 ± 1.8	nt	52.5 ± 1.7	82.6 ± 1.9	65.4 ± 4.1	81.5 ± 1.5
I-6	27.3 ± 1.7	52.6 ± 3.6	70.9 ± 2.4	62.1 ± 2.4	nt	52.5 ± 4.1	82.6 ± 2.8	71.2 ± 2.2	84.6 ± 2.2
I-7	18.2 ± 1.9	52.6 ± 2.7	76.7 ± 0.5	75.9 ± 1.5	nt	45.0 ± 3.3	87.0 ± 3.1	71.2 ± 1.4	90.8 ± 1.5
I-8	22.7 ± 0.3	47.4 ± 3.4	53.5 ± 1.4	75.9 ± 0.4	nt	50.0 ± 2.8	84.8 ± 2.1	67.3 ± 2.1	83.1 ± 1.7
I-9	18.2 ± 0.6	26.3 ± 2.3	69.8 ± 3.2	65.5 ± 3.2	nt	50.0 ± 1.9	89.1 ± 1.9	73.1 ± 5.1	89.2 ± 1.5
I-10	38.1 ± 3.1	57.9 ± 3.1	57.1 ± 4.1	57.1 ± 2.2	41.2 ± 1.7	52.6 ± 1.4	96.8 ± 3.2	80.4 ± 1.5	91.1 ± 2.1
I-14	40.0 ± 5.8	36.4 ± 2.5	66.7 ± 2.4	56.3 ± 1.7	27.3 ± 3.1	46.7 ± 3.5	86.4 ± 2.2	69.2 ± 2.4	65.8 ± 1.7
I-15	40.0 ± 3.6	27.3 ± 1.3	76.2 ± 3.1	43.8 ± 2.4	27.3 ± 2.8	33.3 ± 4.2	90.9 ± 1.5	69.2 ± 3.1	81.6 ± 2.1
I-16	45.0 ± 2.2	27.3 ± 1.0	52.4 ± 2.5	56.3 ± 3.1	31.8 ± 2.5	46.7 ± 4.4	90.9 ± 0.9	56.4 ± 0.9	72.4 ± 2.2
I-17	33.3 ± 1.7	29.4 ± 2.1	83.3 ± 1.3	52.6 ± 2.6	66.7 ± 4.1	43.5 ± 2.3	83.8 ± 1.7	55.2 ± 3.1	62.5 ± 7.2
I-18	68.8 ± 4.1	76.9 ± 4.5	84.0 ± 2.1	55.6 ± 1.9	23.5 ± 2.3	44.4 ± 3.3	90.3 ± 2.2	67.9 ± 4.1	90.3 ± 1.2
I-21	38.5 ± 2.6	58.8 ± 2.3	95.5 ± 0.7	73.7 ± 2.5	60.0 ± 1.9	44.0 ± 1.5	88.6 ± 1.5	74.4 ± 2.2	88.2 ± 1.4
I-23	42.3 ± 2.2	35.3 ± 2.5	100 ± 0	63.2 ± 1.5	60.0 ± 2.1	44.0 ± 2.1	79.5 ± 3.2	81.4 ± 1.6	84.3 ± 1.5
I-33	62.5 ± 1.8	76.9 ± 2.1	92.0 ± 1.4	72.7 ± 1.4	47.1 ± 1.3	50.0 ± 3.7	90.3 ± 1.2	64.3 ± 1.9	77.6 ± 2.3
Chlorothalonil	83.3 ± 0.4	75.0 ± 1.3	92.3 ± 0.3	73.9 ± 0.7	73.1 ± 0.4	81.0 ± 2.5	96.4 ± 0.5	96.1 ± 0.3	96.1 ± 0.7
Carbendazim	100 ± 0	8.3 ± 1.2	97.4 ± 0.5	43.5 ± 4.2	100 ± 0	100 ± 0	100 ± 0	9.8 ± 2.3	100 ± 0

“nt”: not test.

Table 4. The EC₅₀ of some compounds against three fungals (μg/mL).

No	P. piricola	S. sclerotiorum	R. solani
I-10	nt	4.00 ± 0.7	nt
I-18	nt	9.04 ± 1.5	9.49 ± 1.2
I-21	4.19 ± 0.3	8.80 ± 1.2	nt
I-23	7.01 ± 1.1	nt	nt
I-33	3.74 ± 1.6	9.76 ± 1.9	nt
Chlorothalonil	7.33 ± 0.4	5.78 ± 0.8	1.67 ± 0.2

nt: not test.