New peptide derived antimalaria and antimicrobial agents bearing sulphonamide moiety

Figures & data

Scheme 1. Synthesis of glycinediamide derivatives, reagents and conditions. (i) Na₂CO₃, DCM/H₂O, HCl, 0 °C, r.t, Ph 2, 4 h. (ii) EDCI, HOBt, TEA, DCM, amine,16 h. (iii) 10% TFA in DCM. (V)EDCI, HOBt, TEA or DMAP, 16 h.

Table 1. Physicochemical properties of the synthesized compounds.

Mol	HBA	aAc	aA	HBD	Nrb	logP (o/w)	MR	TPSA	MW	LNV	RNV
7a	4	0	44	3	9	2.00	10.17	104.37	395.87	0	1
7b	4	0	44	3	9	1.96	10.17	104.37	395.87	0	1
7c	4	0	44	3	9	1.56	9.74	104.37	379.41	0	1
7d	4	0	44	3	9	1.52	9.74	104.37	379.41	0	1
7e	4	0	47	3	9	1.67	10.12	104.37	375.45	0	1
7f	4	0	44	3	9	1.37	9.67	104.37	361.42	0	1
7g	4	0	50	3	9	2.63	11.29	104.37	411.48	0	1
7h	4	0	47	3	9	2.30	10.63	104.37	409.89	0	1
7i	4	0	47	3	9	2.26	10.63	104.37	409.89	0	1
7j	4	0	47	3	9	1.86	10.20	104.37	393.44	0	1
7k	4	0	47	3	9	1.82	10.20	104.37	393.44	0	1
7l	4	0	50	3	9	1.97	10.57	104.37	389.48	0	1
7m	4	0	47	3	9	1.67	10.12	104.37	375.45	0	1
7n	4	0	53	3	9	2.93	11.74	104.37	425.51	0	1

MW: molecular weight; HBA: hydrogen bond acceptor; HBD: hydrogen bond donor; TPSA: total polar surface area; nRB: number of rotatable bond; nAc: number of acid; MR: molar refractivity; nA: number of atoms; LNV: Lipinski’s number of violations; RNV: Reckitt’s number of violation.

Table 2. Free binding energy (ΔG, kcal/mol) of compounds.

		Malaria Receptors		Bacterial receptors
S/N	Compound	3QS1	1SME	2Y2G	5MMN
1	7a	−11.96	−12.61	−12.88	−10.52
2	7b	−11.66	−11.37	−13.43	−10.58
3	7c	−12.09	−11.75	−13.09	−10.38
4	7d	−11.83	−11.78	−13.34	−10.98
5	7e	−12.16	−12.51	−12.48	−10.72
6	7f	−12.50	−11.43	−12.98	−10.62
7	7g	−12.91	−12.55	−13.69	−10.75
8	7h	−12.34	−12.61	−12.59	−9.95
9	7i	−11.60	−11.24	−12.09	−9.90
10	7j	−11.65	−11.89	−12.41	−10.98
11	7k	−12.01	−11.72	−12.24	−10.81
12	7l	−11.63	−11.99	−11.91	−10.62
13	7m	−12.22	−12.24	−12.60	−10.83
14	7n	−11.99	−11.81	−13.30	−11.11
15	Native ligand	−13.45	−8.82	−13.24	−11.50
16	Standard drug	−11.67	−11.29	−12.32	−9.92

Standard drugs: Chloroquine for antimalarial and penicillin for antibacterial.

Figure 1. A stereoview showing the active site of the 7g-2Y2G complex. 7g is shown in ball-and-stick model (orange). The amino acids are shown as lines (black). Hydrogen and π-H bonds between 7g and the protein are shown as green and purple dotted lines, respectively.

Figure 2. Representation of the chemical interactions of 7g with the amino acid residues of 3QS1.

Figure 3. 2D Representation of the chemical interactions of 7a with the amino acid residues of 1SME.

Figure 4. A stereoview showing the active site of the 7g-2Y2G complex. 7g is shown in ball-and-stick model (orange). The amino acids are shown as lines (black). Hydrogen and π-H bonds between 7g and the protein are shown as green and purple dotted lines, respectively.

Figure 5. Representation of the chemical interactions of 7g with the amino acid residues of 2Y2G.

Figure 6. 2D Representation of the chemical interactions of 7n with the amino acid residues of 5MMN.

Table 3. MIC (minimum inhibitory concentration) mg/ml.

Comps	B. subtilis	E. coli	S. typhi	P. aeruginosa	K. pneumoniae	S. aureus	C. albicans	A. niger
7a	0.219	0.489	0.199	0.398	0.251	4.677	0.0561	1.585
7b	0.129	0.467	0.602	0.257	1.69	0.288	0.135	0.1000
7c	3.467	0.372	2.691	0.457	0.129	–	3.467	–
7d	0.194	0.521	0.476	0.295	0.177	0.489	0.0343	1.995
7e	–	6.327	0.194	3.802	–	0.389	0.0288	2.089
7f	0.155	0.131	4.677	0.354	5.011	0.190	0.214	0.1047
7g	0.141	–	0.079	–	0.166	–	0.0297	0.158
7h	0.214	0.239	1.288	0.616	5.248	0.234	0.034	0.0316
7i	0.214	0.239	1.288	0.616	5.248	0.234	0.034	0.0316
7j	0.245	0.275	0.129	0.380	0.083	–	0.371	–
7k	0.371	0.316	3.161	3.162	0.079	0.387	0.0631	0.316
7l	0.245	0.169	0.057	0.169	0.107	0.115	0.174	0.123
7m	0.129	0.123	0.057	0.144	0.138	0.229	7.94	0.056
7n	–	0.123	0.617	0.129	–	–	0.155	0.039
CIP	0.184	0.131	0.128	0.232	0.113	0.252	–	–
FLU	–	–	–	–	–	–	0.0217	0.0471

– : No activity; CIP means Ciprofloxacin; FLU means Fluconazole.

Table 4. In vitro antimalarial study.

Compounds	MIC (µM)
7a	0.37
7b	0.87
7c	0.72
7d	0.08
7e	0.05
7f	2.32
7g	3.23
7h	0.03
7i	0.77
7j	0.88
7k	0.53
7l	0.93
7m	1.87
7n	2.34
Chloroquine	0.08
Artemisimin	0.72

Table 5. Percentage inhibition of parasite in mice.

Comp	% inhibition 7 days post-treatment (100 mg/kg)	% inhibition 7 days post-treatment (200 mg/kg)	% inhibition 12 days post-treatment (100 mg/kg)	% inhibition 12 days post-treatment (200 mg/kg)
7a	36.23	52.11	49.97	61.37
7b	51.33	57.62	55.23	53.4
7c	48.32	40.22	51.33	48.71
7d	53.62	48.73	81.72	55.98
7e	62.34	40.22	66.71	50.71
7f	38.23	70.97	41.87	73.29
7g	27.54	54.69	36.83	51.93
7h	61.36	49.85	57.77	55.22
7i	51.73	66.57	46.37	81.38
7j	77.93	77.36	82.68	73.55
7k	40.35	54.92	44.28	56.43
7l	38.23	60.72	41.73	74.62
7m	33.46	71.36	29.33	73.98
7n	47.8	63.8	49.11	71.66
Arte	75.67	78.87	86.22	82.34
NTC	–	–	–	–
NIC	–	–	–	–

Arte: Artemisinin; NIT: Non treated control; NIC: Non infected control.

Table 6. Liver function test.

	ALT (µ/L)		AST (µ/L)		T.P. (g/dl)		Bilirubin (mg/dl)		Glucose (g/l)
Comp	Before	After	Before	After	Before	After	Before	After	Before	After
7e	24.0	22.0	64.0	60.5	5.8	4.5	0.3	0.2	5.8	5.0
7d	24.2	22.5	64.0	68.5	5.7	4.0	0.3	0.2	5.8	5.5
7j	26.3	25.5	65.0	60.0	6.0	5.8	0.4	0.2	5.9	5.7
7h	25.4	24.5	65.0	69.5	6.0	5.5	0.4	0.3	5.9	5.5
7c	20.5	23.5	62.0	61.5	5.8	5.5	0.3	0.5	5.6	5.0
Control	24.2		65.5		5.9		0.3		6.3

Table 7. Kidney function test.

	Creatinine (mg/dl)		Albumin (g/dl)
Compound	Before	After	Before	After
7e	0.3	0.3	4.1	3.5
7d	0.4	0.3	4.0	3.5
7j	0.4	0.3	3.9	4.0
7h	0.3	0.3	3.9	3.9
7c	0.3	0.3	3.5	3.0
Control	0.3		3.9

Table 8. Heamotological analysis before and after treatment.

	RBC (mm^3)		PCV (%)		WBC (mm^3)		HB (g/dl)
Comp	Before	After	Before	After	Before	After	Before	After
7e	6.85 × 10^6	6.0 × 10^6	36	35	12.2 × 10^3	10.5 × 10^3	14.1	11.0
7d	6.82 × 10^6	6.8 × 10^6	37	34	13.5 × 10^3	9.5 × 10^3	13.5	10.5
7j	7.1 × 10^6	6.5 × 10^6	39	34	8.0 × 10^3	9.1 × 10^3	13.5	10.0
7h	7.3 × 10^6	5.9 × 10^6	39	34	9.4 × 10^3	9.3 × 10^3	13.4	10.0
7c	7.5 × 10^6	6.0 × 10^6	38	33	10.3 × 10^3	9.0 × 10^3	14.5	9.8