Characterisation of twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides with QSAR analysis and antimicrobial activity tests

Bogdanović, Aleksandra; Lazić, Anita; Grujić, Slavica; Dimkić, Ivica; Stanković, Slaviša; Petrović, Slobodan

doi:10.2478/aiht-2021-72-3483

Figures & Tables

Structural formula of the investigated N-(substituted phenyl)-2-chloroacetamides

Melting point and yield of N-(substituted phenyl) chloroacetamides

Compound	Substituent	Melting point (ºC)	Yield (%)
SP1	H	136–137	86
SP2	4-CH₃	160–162	89
SP3	4-OCH₃	117–119	84
SP4	4-Cl	166–168	65
SP5	4-Br	178–180	88
SP6	4-F	128–130	83
SP7	4-I	192–195	72
SP8	4-CH₃CO	144–145	64
SP9	4-OH	144–146	76
SP10	4-CN	180–183	56
SP11	3-CN	165–170	61
SP12	3-Br	110–113	83

1H and 13C NMR spectral data

N-phenyl chloroacetamide (SP1)	¹H NMR (CDCl₃): δ 4.272 (2H, s, Cl-CH₂), 7.057–7.130 (1H, t, J_HH = 7.4 Hz, Ar-4H), 7.302–7.380 (2H, t, J_HH = 7.8 Hz, Ar-H), 7.597–7.636 (2H, d, J_HH = 7.8 Hz, Ar-H), 10.321 (1H, s, NH). ₁₃C NMR (CDCl₃): δ 43.833 (Cl-CH₂), 119.651 (C₂,C₅), 124.130 (C₄) 129.119 (C₃,C₅), 138.751 (C₁), 164.934 (C=O).
N-(4-methylphenyl) chloroacetamide (SP2)	¹H NMR (CDCl₃): δ 2.255 (2H, s, CH₃), 4.421 (1H, s, Cl-CH₂), 7.111–7.153 (2H, d, J_HH = 8.2 Hz, Ar-H), 7.473–7.515 (2H, d, J_HH = 8.2 Hz, Ar-H), 10.222 (1H, s, NH). ¹³C NMR (CDCl₃): δ 20.655 (CH₃), 43.797 (Cl-CH₂), 119.614 (C₂,C₆), 129.483 (C₃,C₅), 133.088 (C₁), 136.238 (C₄), 164.643 (C=O).
N-(4-metoxylphenyl) chloroacetamide (SP3)	¹H NMR (CDCl₃): δ 3.729 (2H, s, OCH₃), 4.229 (1H, s, Cl-CH₂), 6.886–6.948 (2H, d, J_HH = 9.0 Hz, Ar-H), 7.481–7.560 (2H, d, J_HH = 9.0 Hz, Ar-H), 10.177 (1H, s, NH).). ¹³C NMR (CDCl₃): δ 43.742 (Cl-CH₂), 55.359 (OCH₃), 114.189 (C₃,C₅), 121.217 (C₂,C₆), 131.814 (C₁), 155.885(C₄), 164.424 (C=O).
N-(4-chlorophenyl) chloroacetamide (SP4)	¹H NMR (CDCl₃): δ 4.280 (1H, s, Cl-CH₂), 7.358–7.431 (2H, d, J_HH = 9.0 Hz, Ar-H), 7.613–7.686 (2H, d, J_HH = 9.0 Hz, Ar-H), 10.445 (1H, s, NH), ¹³C NMR (CDCl₃): δ 43.741 (Cl-CH₂), 121.162 (C₂,C₆), 129.010 (C₃,C₅), 137.677 (C₁), 165.061 (C=O).
N-(4-bromophenyl) chloroacetamide (SP5)	¹H NMR (CDCl₃): δ 4.274 (1H, s, Cl-CH₂), 7.495–7.616 (4H, m, Ar-H), 10.447 (1H, s, N-H). ¹³C NMR (CDCl₃): δ 43.742 (Cl-CH₂), 115.736 (C₄), 121.526 (C₂,C₆), 131.923 (C₃,C₅), 138.095 (C₁), 165.061 (C=O).
N-(4-fluorophenyl) chloroacetamide (SP6)	¹H NMR (CDCl₃): δ 4.369 (1H, s, Cl-CH₂), 7.122–7.226 (2H, t, J_HH = 9.0 Hz, Ar-H)), 7,588–7,675 (2H, m, Ar-H), 10,337 (1H, s, NH). ¹³C NMR (CDCl₃): δ 43.688 (Cl-CH₂), 115.463–115.900 (C₃,C₅), 121.381 (C₂,C₆), 135.073 (C₁), 160.983 (C₄), 164.861 (C=O).
N-(4-iodophenyl) chloroacetamide (SP7)	¹H NMR (CDCl₃): δ 4.263 (1H, s, Cl-CH₂), 7.425–7.4709 (2H, d, J_HH = 9.0 Hz, Ar-H), 7,658–7,701 (2H, d, J_HH = 9.0 Hz, Ar-H), 10.416 (1H, s, NH). ¹³C NMR (CDCl₃): δ 43.760 (Cl-CH₂), 87.732 (C₄), 121.745 (C₂,C₆), 137.750–138.551 (C₃,C₅), 165.043 (C=O).
N-(4-acetylphenyl) chloroacetamide (SP8)	¹H NMR (CDCl₃): δ 2.544 (3H, s, CH₃), 4.328 (1H, s, Cl-CH₂), 7,723–7,768 (2H, d, J_HH = 9.0 Hz, Ar-H), 7.945–7.990 (2H, d, J_HH = 9.0 Hz, Ar-H), 10.646 (1H, s, NH). ¹³C NMR (CDCl₃): δ 26.645 (CH₃), 43.833 (Cl-CH₂), 118.868 (C₂,C₆), 129.793 (C₃,C₅), 132.451 (C₄), 143.030 (C₁), 165.462 (C=O), 196.798 (COCH₃).
N-(4-hydroxyphenyl) chloroacetamide (SP9)	¹H NMR (CDCl₃): δ 4.280 (2H, s, Cl-CH₂), 4.684 (1H, s, OH), 7.139–7.184 (2H, d, J_HH = 9.0 Hz, Ar-H), 7.625–7.686 (2H, d, J_HH = 8.8 Hz, Ar-H). ¹³C NMR (CDCl₃): δ 43.706 (Cl-CH₂), 120.671(C₃,C₅), 122.091 (C₂,C₆), 136.7489 (C₁), 146.180 (C₄), 164.989–166.791 (C=O).
N-(4-cyanophenyl) chloroacetamide (SP10)	¹H NMR (CDCl₃): δ 4.319 (2H, s, Cl-CH₂), 7.552–7.619 (2H, d, J_HH = 9.0 Hz, Ar-H), 7.782–7.877 (2H, d, J_HH = 9.0 Hz, Ar-H), 10.745 (1H, s, 2-H). ¹³C NMR (CDCl₃): δ 43.669 (Cl-CH₂), 111.985 (C₃), 118.668 (CN), 122.309 (C₂), 124.203 (C₆), 127.662 (C₄), 130.321–130.594 (C₅), 139.516 (C₁), 165.589 (C=O).
N-(3-cyanophenyl) chloroacetamide (SP11)	¹H NMR (CDCl₃): δ 4.339 (1H, s, Cl-CH₂), 7.552–7.619 (2H, d, J_HH = 5.6 Hz, Ar-H), 7.782–7.813 (1H, m, Ar-H), 8.094 (1H, s, Ar-H), 10.745 (1H, s, NH). ¹³C NMR (CDCl₃): δ 43.669 (Cl-CH₂), 111.985 (C₃), 118.668 (CN), 122.309 (C₂), 124.203 (C₆), 127.662 (C₄), 130.321–130.594 (C₅), 139.516 (C₁), 165.589 (C=O).
N-(3-bromophenyl) chloroacetamide (SP12)	¹H NMR (CDCl₃): δ 4.286 (3H, s, Cl-CH₂), 7.285–7.358 (2H, m, Ar-H), 7.470– 7.571 (1H, m, Ar-H), 7.962 (1H, s, Ar-H), 10.489 (1H, s, N-H). ¹³C NMR (CDCl₃): δ 43.688 (Cl-CH₂), 118.376 (C₂), 121.836 (C5), 121.927 (C₆), 126.697 (C₄), 131.067 (C₃), 140.262 (C₁), 165.243 (C=O).

Partition coefficients of the studied chloroacetamides

Compound	logP (22)	logP_o/w(XLOGP3) (23)	logP_o/w(WLOGP) (23)	logP_o/w(MLOGP) (23)
SP1	1.72	1.63	1.67	1.84
SP2	2.17	1.99	1.98	2.15
SP3	1.78	1.65	1.68	1.54
SP4	2.40	2.26	2.33	2.42
SP5	2.53	2.32	2.44	2.56
SP6	1.89	1.73	2.23	2.27
SP7	2.81	2.28	2.28	2.71
SP8	1.62	1.86	1.88	1.47
SP9	1.24	1.27	1.38	1.23
SP10	1.45	1.82	1.54	1.18
SP11	1.48	1.35	1.54	1.18
SP12	2.51	2.93	2.44	2.56
Levetiracetam	0.69	0.62	-0.03	0.28
Piracetam	-1.32	-1.54	-1.29	-0.96

Physicochemical properties of the studied chloroacetamides

Compound	Molecular weight (g/ mol)	Number of atoms	Number of rotatable bonds	Number of hydrogen bond donors	Number of hydrogen bond acceptors	Molar refractivity	Topological polar surface area (Å²)
SP1	169.61	11	3	1	2	45.55	29.10
SP2	183.63	12	3	1	2	50.52	29.10
SP3	199.63	13	4	1	3	52.04	38.33
SP4	204.05	12	3	1	2	50.56	29.10
SP5	248.50	12	3	1	2	53.25	29.10
SP6	187.60	12	3	1	2	45.51	29.10
SP7	295.50	12	3	1	2	58.27	29.10
SP8	211.64	14	4	1	3	55.75	46.17
SP9	185.61	12	3	2	3	47.57	49.33
SP10	194.62	13	3	1	3	50.27	52.89
SP11	194.62	13	3	1	3	50.27	52.89
SP12	248.50	12	3	1	3	53.25	29.10
Levetiracetam	156.23	11	3	1	2	48.17	46.33
Piracetam	142.16	10	2	1	2	38.76	63.40

QSAR biophysical-kinetic profiles of the compounds related to metabolism properties

Prediction tool	SwissADME	pkCSM	Swiss ADME	pkCSM	SwissADME	pkCSM	SwissADME	pkCSM	SwissADME	pkCSM
Compound	Inhibits CYP1A2	Inhibits CYP1A2	Inhibits CYP2C19	Inhibits CYP2C19	Inhibits CYP2C9	Inhibits CYP2C9	Inhibits CYP2D6	Inhibits CYP2D6	Inhibits CYP3A4	Inhibits CYP3A4
SP1	Yes	No	No	No	No	No	No	No	No	No
SP2	Yes	Yes	No	No	No	No	No	No	No	No
SP3	Yes	Yes	No	No	No	No	No	No	No	No
SP4	Yes	Yes	No	No	No	No	No	No	No	No
SP5	Yes	Yes	No	No	No	No	No	No	No	No
SP6	Yes	Yes	No	No	No	No	No	No	No	No
SP7	Yes	Yes	No	No	No	No	No	No	No	No
SP8	Yes	Yes	No	No	No	No	No	No	No	No
SP9	No	No	No	No	No	No	No	No	No	No
SP10	Yes	Yes	No	No	No	No	No	No	No	No
SP11	Yes	Yes	No	No	No	No	No	No	No	No
SP12	Yes	Yes	No	No	No	No	No	No	No	No
Levetiracetam	No	No	No	No	No	No	No	No	No	No
Piracetam	No	No	No	No	No	No	No	No	No	No

Characterisation of investigated N-(substituted phenyl)-2-chloroacetamides

Comp	R	IR (KBr) ν_max (cm^-1)
SP1	H	3267 (N-H); 3207, 3145, 3098 (C-H aromatic ring); 2947 (C-H); 1671 (C=O); 1618 (C=C); 1557 (N-H deformation); 1498, (C-H bending); 1443 (C-H bending); 1344 (C-H); 1251 (C-N); 749 (N-H).
SP2	4-CH₃	3273 (N-H); 3204, 3135, 3090 (C-H aromatic ring); 2954 (C-H); 1673 (C=O); 1616 (C=C); 1554 (N-H); 1402 (C-H); 1343 (C-H); 1251 (C-N); 818 (N-H).
SP3	4-OCH₃	3295 (N-H); 3139, 3073 (C-H aromatic ring); 2957 (C-H); 2909 2835 (C-H); 1663 (C=O); 1612 (C=C); 1547 (N-H); 1510 (N-H); 1465 (C-H); 1413 (C-H); 1247 (C-N); 830 (N-H).
SP4	4-Cl	3264(N-H); 3199, 3131, 3082 (C-H aromatic ring); 3005, 2952(C-H); 1669 (C=O); 1614 (C=C); 1551 (N-H); 1490 (C-H); 1400 (C-H); 1248 (C-N); 825 (N-H).
SP5	4-Br	3263 (N-H); 3194 (C-H); 3125, 3077 (C-H aromatic ring); 3000 2953 (C-H); 1669 (C=O); 1549 (N-H); 1488 (C-H); 1395 (C-H); 1248 (C-N); 822 (N-H).
SP6	4-F	3275, 3221 (N-H); 3165 (C-H aromatic ring); 2947 (C-H); 1668 (C=O); 1508 (N-H); 1406 (C-H); 1292; 1212 (C-N); 832 (N-H).
SP7	4-I	3309, 3270 (N-H); 3194, 3077 (C-H aromatic ring); 2936 (C-H); 2953 (C-H); 1672 (C=O); 1610 (N-H); 1543 (C-H); 1392–1089 (CH); 1245 (C-N); 817 (N-H).
SP8	4-COCH₃	3325, 3286 (N-H); 3196, 3109 (C-H aromatic ring); 2922, 2857 (C-H); 1707 (C=O); 1655 (C=C); 1599 (N-H); 1539 (C-H); 1283 (C-O); 1252 (C-N); 834 (N-H).
SP9	4-OH	3296 (O-H); 3144 (N-H); 3098 (C-H); 1677 (C=O); 1508 (N-H); 1313 (C-H); 1211 (C-N); 820 (N-H).
SP10	4-CN	3265 (N-H); 3192, 3119 (C-H); 2946 (C-H); 2226 (C?N); 1681 (C=O); 1603 (C=C); 1539 (N-H); 1408, 1345 (C-H); 1256 (C-N); 839 (N-H).
SP11	3-CN	3265 (N-H); 3096 (C-H); 2964 C-H); 2232 (C?N); 1678 (C=O); 1610 (C=C); 1561 (N-H); 1485 (C-H); 1293 (C-N); 1089 (C-H); 799 (N-H).
SP12	3-Br	3268 (N-H); 3193, 3127 (C-H); 2945 (C-H); 1679 (C=O); 1594 (N-H); 1424 (C-H); 1249 (C-N); 779 (N-H).

QSAR pharmacokinetic profiles of the selected compounds related to absorption properties

Compound	SwissADME	pkCSM	SwissADME	PreADMET	SwissADME	PreADMET
	Gastrointestinal absorption	Intestinal absorption (%)	the compound penetrates the blood-brain barrier	The compound penetrating the blood-brain barrier (c_brain/c_blood)	the compound is a P-gp inhibitor	the compound is a P-gp inhibitor
	SP1	High	91.156	Yes	0.902206	No	No
SP2	High	91.692	Yes	2.16896	No	No
SP3	High	93.810	Yes	0.612824	No	No
SP4	High	91.969	Yes	1.65555	No	No
SP5	High	91.902	Yes	1.79202	No	No
SP6	High	91.217	Yes	1.07913	No	No
SP7	High	90.802	Yes	1.52595	No	No
SP8	High	92.635	Yes	0.546121	No	No
SP9	High	90.745	Yes	0.975597	No	No
SP10	High	92.986	Yes	0.975597	No	No
SP11	High	92.817	Yes	0.975597	No	No
SP12	High	92.405	Yes	1.79204	No	No
Levetiracetam	High	86.852	No	0.440234	No	No
Piracetam	High	86.061	No	0.165163	No	No

Minimum inhibitory, bactericidal, and fungicidal concentrations of N-(substituted phenyl)-2-chloroacetamides (means ± standard errors)

Tested substances	R	C. albicans	E. coli	S. aureus	MRSA
Tested substances	R	MIC (μg/mL)
SP1	4-H	190±40^c	920±80^c	90±20^c	50±0^cd
SP2	4-CH₃	330±110^c	3330±330^ab	60±0^c	60±0^cd
SP3	4-OCH₃	190±40^c	540±110^c	110±10^c	190±40^bc
SP4	4-Cl	60±0^c	3670±330^ab	60±0^c	90±20^bcd
SP5	4-Br	330±80^c	4000±0^a	60±0^c	60±0^cd
SP6	4-F	110±10^c	500±140^c	150±50^bc	110±10^bcd
SP7	4-I	830±170^c	2670±330^b	40±10^c	40±10^d
SP8	4-COCH₃	330±80^c	330±80^c	190±40^bc	90±20^bcd
SP9	4-OH	2660±670^a	270±20^c	130±0^c	40±10^d
SP10	3-CN	290±40^c	190±40^c	40±10^c	90±20^bcd
SP11	4-CN	230±20^c	1000±290^c	750±140^a	220±20^ab
SP12	3-Br	100±20^c	500±140^c	80±20^c	90±20^bcd
Ant/Myc	–	2000±0^ab	90±10^c	40±10^c	70±20^cd
MBC/MFC (μg/mL)
SP1	4-H	500±0^c	2000±0^b	250±0^bcd	120±0^c
SP2	4-CH₃	670±170^c	4000±0^a	170±40^cd	310±110^c
SP3	4-OCH₃	330±80^c	1000±0^c	250±0^bcd	330±80^c
SP4	4-Cl	2000±0^b	Nd	130±0^d	750±140^bc
SP5	4-Br	4000±0^a	Nd	420±80^bcd	750±140^bc
SP6	4-F	330±80^c	1000±0^c	750±140^bc	250±0^c
SP7	4-I	3000±580^ab	4000±0^a	130±0^d	290±110^c
SP8	4-COCH₃	670±170^c	670±170^d	750±140^bc	330±80^c
SP9	4-OH	4000±0^a	500±0^d	330±80^bcd	170±40^c
SP10	3-CN	500±0^c	420±80^d	130±0^d	250±0^c
SP11	4-CN	500±0^c	2000±0^b	2330±330^a	1330±330^ab
SP12	3-Br	670±170^c	1000±0^c	210±40^cd	330±80^c
Ant/Myc	–	Nd	130±30^e	100±0^d	100±0^c

Characterisation of twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides with QSAR analysis and antimicrobial activity tests

Figures & Tables

Figure 1

Melting point and yield of N-(substituted phenyl) chloroacetamides

1H and 13C NMR spectral data

Partition coefficients of the studied chloroacetamides

Physicochemical properties of the studied chloroacetamides

QSAR biophysical-kinetic profiles of the compounds related to metabolism properties

Characterisation of investigated N-(substituted phenyl)-2-chloroacetamides

QSAR pharmacokinetic profiles of the selected compounds related to absorption properties

Minimum inhibitory, bactericidal, and fungicidal concentrations of N-(substituted phenyl)-2-chloroacetamides (means ± standard errors)

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