Evaluation of anti-bacterial activity of novel 2, 3-diaminoquinoxaline derivatives: design, synthesis, biological screening, and molecular modeling studies

Figures & data

Figure 1. The certain examples of Quinoxaline-based drugs against various targets.

Table 1. Compounds of the scheme-1 (1–4 series) (N²-alkyl-N³-phenylquinoxaline-2,3-diamine derivatives): reaction time, yield, and M.P. of each compound

Entry	Compound	R1	R2	R3	Time (h)	Yield (%)	M.P.(°C)
1.	4a	H	H	H	12 h	87.00%	245–246
2.	4b	H	H	CF3	12 h	91.00%	237–238
3.	4c	H	H	F	8 h	86.14%	254–256
4.	4d	H	H	Cl	8 h	85.10%	238–240
5.	4e	H	H	CH3	8 h	90.90%	245–246
6.	4 f	H	H	OCH3	8 h	89.55%	135–136
7.	4g	H	H	Br	8 h	83.83%	242–243
8.	4 h	H	F	H	6 h	89.55%	258–261
9.	4i	H	Cl	H	6 h	86.87%	250–251
10.	4 j	H	Br	H	6 h	85.32%	246–247
11.	4k	H	CH3	H	8 h	90.15%	250–251
12.	4 l	H	OCH3	H	6 h	87.45%	228–229
13.	4 m	CH3	H	H	12 h	45.45%	148–149
14.	4 n	H	CF3	H	12 h	83.06%	232–233
15.	4o	H	H	CN	12 h	83.94%	231–233
16.	4p	H	H	CF3	12 h	76.28%	276–278
17.	4q	H	H	Cl	8 h	86.17%	275–277
18.	4 r	H	H	OCH3	8 h	92.08%	245–246
19.	4s	H	H	CF3	12 h	75.01%	276–277
20.	4 t	H	H	Cl	8 h	86.33%	280–281
21.	4 u	H	H	OCH3	8 h	89.41%	248–250
22.	4 v	H	H	H	12 h	89.79%	265–267
23.	4 w	H	H	Cl	12 h	87.59%	275–276
24.	4x	H	H	CF3	12 h	80.00%	276–277
25.	4y	H	H	CH3	8 h	86.38%	280–281
26.	4z	H	H	OCH3	8 h	92.59%	245–246

Scheme 1. Reagents and conditions: (a) (COOH)₂.2H₂O, 4 N HCl, 100°C, 6 h; (b) SOCl₂, DCE, Cat. DMF, 100°C, 6 h; (c) Alkyl amine (derivatives), K₂CO₃, DMF, rt, 12 h; (d) Aniline (derivatives), ethanol, reflux, 12 h.

Figure 2. Novel designed from the privileged structure (a) Antibacterial activity from DNA intercalators [66] (b) Hydrazine binding with specific amino acid of Dihydrofolate reductase protein. [67].

Table 2. Antimicrobial and antifungal activity, zone of inhibition (mm)

Comp. No.	S. aureus	B. subtillis	E. coli	K. pneumoniae	S. typhi	C. albicans	A. Niger
4b	10.88	10.56	10.66	10.56	Nt	10.12	7.11
4c	10.56	14.89	14.28	10.11	Nt	11.33	7.02
4 h	11.16	14.11	11.51	10.30	12.91	7.11	Nt
4 l	9.33	10.12	10.92	11.22	7.92	8.14	Nt
4 m	7.12	9.33	9.74	7.00	Nt	8.12	7.06
4 n	12.72	12.53	10.11	9.85	12.53	7.25	Nt
4 w	9.94	10.27	9.89	8.56	11.15	8.17	Nt
4x	9.81	10.54	9.20	7.12	9.9	7.24	Nt
4z	7.92	8.32	7.12	7.14	7.15	7.1	Nt
Ch.	19.45	24.55	27.36	24.53	28.32	NA	NA
Am.	NA	NA	NA	NA	NA	18.00	22.13

Table 3. Physicochemical property estimation (QikProp properties) of new designs

Comp. No.	M.Wt	Donor HB	Acceptor HB	PSA	Rule of Five*
4b	344.33	10.56	10.66	40.36	1
4c	294.33	14.89	14.28	40.37	0
4 h	294.33	14.11	11.51	40.38	0
4 l	306.36	10.12	10.92	48.53	0
4 m	290.36	9.33	9.74	39.13	0
4 n	344.33	12.53	10.11	40.43	1
4 w	338.83	10.27	9.89	38.98	1
4x	372.39	10.54	0	38.99	1
4z	334.42	8.32	7.12	47.27	0
Ch.	323.13	26.12	25.88	120.24	0

M.Wt; molecular weight. Donor HB; estimated number of hydrogen bonds that would be donated by the solute to water molecules in an aqueous solution (0.0–6.0). Acceptor HB; estimated number of hydrogen bonds that would be accepted by the solute from water molecules in an aqueous solution (2.0–20.0).*; violations of Lipinski’s rule of five. PSA; Van der Waals surface area of polar nitrogen, oxygen and carbonyl carbon atoms. Ch; Chloramphenicol.

Table 4. Docking scores, residue contacts and ∆G of binding scores of proposed designs. Ch; Chloramphenicol

Comp. No.	Docking scores	Residue contacts	∆G of binding
4b	−6.45	Ser-1084; DG (G):9; DA (H): 13	−42.01
4c	−6.11	Ser-1084; DG (G):9; DA (H): 13	−12.82
4 h	−6.06	Ser-1084; DG (G):9; DA (H): 13	−24.53
4 l	−6.21	Ser-1084; DG (G):9; DA (H): 13	−35.96
4 m	−5.06	Ser-1084; DG (G):9	−17.56
4 n	−5.93	Ser-1084; DG (G):9; DA (H): 13	0.57
4 w	−6.55	Ser-1084; DG (G):9; DA (H): 13; Arg-4548	−11.74
4x	−6.54	Ser-1084; DG (G):9; DA (H): 13	−26.27
4z	−6.68	Ser-1084; DG (G):9; DA (H): 13	−40.71
Ch.	−7.18	Ser-1084; DT (E):8;	−50.26

Figure 3. The comparison between the inhibition zones of compounds (4b-4z) and standard drugs against bacterial and fungal strains.

Figure 4. Docking poses of our 2,3-diamino quinoxaline designs (A-H) at the quinolone-binding site of S. aureus DNA gyrase. Consistency in binding interactions with protein (Ser-1084) and DNA base pairs DG (G):9; DA (H): 13 and posing adjucent to Mg⁺² ion can be seen for all the new designs.

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