Design, molecular docking, synthesis, characterization, biological activity evaluation (against MES model), <i>in-silico</i> biological activity spectrum (PASS analysis), toxicological and predicted oral rat LD<sub>50</sub> studies of novel sulphonamide derivatives

doi:10.1007/s11515-018-1512-4

Front. Biol.

2018, Vol. 13

Issue (6) : 425-451 https://doi.org/10.1007/s11515-018-1512-4

RESEARCH ARTICLE

Design, molecular docking, synthesis, characterization, biological activity evaluation (against MES model), in-silico biological activity spectrum (PASS analysis), toxicological and predicted oral rat LD₅₀ studies of novel sulphonamide derivatives

Ajeet¹(

), Arvind Kumar², Arun K. Mishra¹

¹. Drug Design Laboratory, School of Pharmaceutical Sciences, IFTM University, Moradabad, Uttar Pradesh, India
². Department of Pharmaceutical Chemistry, S. D. College of Pharmacy and Vocational Studies, Muzaffarnagar, Uttar Pradesh, India

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Abstract

BACKGROUND: Among the reported potential agents to treat the epilepsy, sulphonamides are important and their significance cannot be ignored. A series of substituted 4-amino-benzene sulfonamides were designed, keeping in view the structural requirement of pharmacophore.

METHODS: Lipinski rule of five has been calculated; failure to Lipinski rule was not observed. Docking was performed through AutoDock Vina. Molecules have been screened out through docking. Compounds were synthesized and characterized through IR, ¹HNMR, ¹³C NMR, Mass and elemental analysis. The anticonvulsant activity of the synthesized compounds was assessed using the Maximal Electroshock Seizure (MES) model. In-silico biological activity spectrum, toxicological studies, predicted oral rats LD50 were performed.

RESULTS: Docking studies showed good interaction with lyase (Oxo-acid) - human carbonic anhydrase-I (1AZM). The in-silico studies proved them to be with good drug-likeness properties, especially 4-(3-Acetyl-phenylamino)-methyl)-benzenesulfonamide (2g). These results revealed that the synthesized compounds (1a-1c, 2a-2q) exhibited promising anticonvulsant effect against MES model for inhibition of Lyase- Human Carbonic Anhydrase-I.

CONCLUSION: After investigating all the results, the compound 4-(3-Acetyl-phenylamino)-methyl)-benzenesulfonamide (2g) is found to be best in the series. A comparatively good activity of compound 2g suggests us that sulphonamide can be leads to further optimization for building potent and chemically diversified anti-convulsant agents.

Keywords anticonvulsant sulfonamide docking in-silico studies

Corresponding Author(s): Ajeet

Online First Date: 23 August 2018 Issue Date: 30 November 2018

Cite this article:

Ajeet,Arvind Kumar,Arun K. Mishra. Design, molecular docking, synthesis, characterization, biological activity evaluation (against MES model), in-silico biological activity spectrum (PASS analysis), toxicological and predicted oral rat LD₅₀ studies of novel sulphonamide derivatives[J]. Front. Biol., 2018, 13(6): 425-451.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-018-1512-4
https://academic.hep.com.cn/fib/EN/Y2018/V13/I6/425

Tab.1 Pharmacophoric pattern of well-known anticonvulsants

Fig.12 Scheme 1. Synthetic scheme of substituted 4-amino-benzenesulfonamide from substituted acids (1a-1c)

Fig.13 Scheme 2. Synthetic scheme of substituted 4-amino-benzenesulfonamide from (Chloro-substituted)-substituted benzene (2a-2q)

Fig.14 Common reaction mechanism of schemes employed.

Tab.2 Designed molecules

Tab.3 Descriptors of Lipinski Rule of Five

Ligand	Affinity kcal/mol	H- bond	H- binding ligand			H- binding receptor
Ligand	Affinity kcal/mol	H- bond	Elem	At. ID	Type	Residue	Elem	At.ID	Type
1a	-7.7	6	O	19	Acceptor	Thr199	N	196	Donor
			O	19	Acceptor	Thr199	O	201	Both
			N	20	Donor	Thr199	O	201	Both
			N	20	Donor	His96	N	94	Acceptor
			N	20	Donor	His94	N	82	Acceptor
			O	18	Acceptor	His119	N	113	Donor
1b	-7.7	7	O	21	Acceptor	Thr199	N	196	Donor
			O	21	Acceptor	Thr199	O	201	Both
			N	22	Donor	Thr199	O	201	Both
			N	22	Donor	His96	N	94	Acceptor
			N	22	Donor	His94	N	82	Acceptor
			O	20	Acceptor	His119	N	113	Donor
			O	9	Acceptor	Gln92	N	69	Donor
1c	-7.2	7	O	18	Acceptor	Thr199	N	196	Donor
			O	18	Acceptor	Thr199	O	201	Both
			N	19	Donor	Thr199	O	201	Both
			N	19	Donor	His96	N	94	Acceptor
			N	19	Donor	His94	N	82	Acceptor
			O	17	Acceptor	His119	N	113	Donor
			O	9	Acceptor	Gln92	N	69	Donor
2a	-7.3	6	O	21	Acceptor	Thr199	N	196	Donor
			O	21	Acceptor	Thr199	O	201	Both
			N	22	Donor	Thr199	O	201	Both
			N	22	Donor	His96	N	94	Acceptor
			N	22	Donor	His94	N	82	Acceptor
			O	20	Acceptor	His119	N	113	Donor
2b	-7.3	6	O	20	Acceptor	Thr199	N	196	Donor
			O	20	Acceptor	Thr199	O	201	Both
			N	21	Donor	Thr199	O	201	Both
			N	21	Donor	His96	N	94	Acceptor
			N	21	Donor	His94	N	82	Acceptor
			O	19	Acceptor	His119	N	113	Donor
2c	-7.3	6	O	20	Acceptor	Thr199	N	196	Donor
			O	20	Acceptor	Thr199	O	201	Both
			N	21	Donor	Thr199	O	201	Both
			N	21	Donor	His96	N	94	Acceptor
			N	21	Donor	His94	N	82	Acceptor
			O	19	Acceptor	His119	N	113	Donor
2d	-7.3	6	O	20	Acceptor	Thr199	N	196	Donor
			O	20	Acceptor	Thr199	O	201	Both
			N	21	Donor	Thr199	O	201	Both
			N	21	Donor	His96	N	94	Acceptor
			N	21	Donor	His94	N	82	Acceptor
			O	19	Acceptor	His119	N	113	Donor
2e	-7.3	6	O	21	Acceptor	Thr199	N	196	Donor
			O	21	Acceptor	Thr199	O	201	Both
			N	22	Donor	Thr199	O	201	Both
			N	22	Donor	His96	N	94	Acceptor
			N	22	Donor	His94	N	82	Acceptor
			O	20	Acceptor	His119	N	113	Donor
2f	-7.2	6	O	21	Acceptor	Thr199	N	196	Donor
			O	21	Acceptor	Thr199	O	201	Both
			N	22	Donor	Thr199	O	201	Both
			N	22	Donor	His96	N	94	Acceptor
			N	22	Donor	His94	N	82	Acceptor
			O	20	Acceptor	His119	N	113	Donor
2g	-7.4	6	O	21	Acceptor	Thr199	N	196	Donor
			O	21	Acceptor	Thr199	O	201	Both
			N	22	Donor	Thr199	O	201	Both
			N	22	Donor	His96	N	94	Acceptor
			N	22	Donor	His94	N	82	Acceptor
			O	20	Acceptor	His119	N	113	Donor
2h	-7.2	6	O	10	Acceptor	Thr199	N	196	Donor
			O	10	Acceptor	Thr199	O	201	Both
			N	11	Donor	Thr199	O	201	Both
			N	11	Donor	His96	N	94	Acceptor
			N	11	Donor	His94	N	82	Acceptor
			O	9	Acceptor	His119	N	113	Donor
2i	-7.2	6	O	10	Acceptor	Thr199	N	196	Donor
			O	10	Acceptor	Thr199	O	201	Both
			N	11	Donor	Thr199	O	201	Both
			N	11	Donor	His96	N	94	Acceptor
			N	11	Donor	His94	N	82	Acceptor
			O	9	Acceptor	His119	N	113	Donor
2j	-7.4	6	O	10	Acceptor	Thr199	N	196	Donor
			O	10	Acceptor	Thr199	O	201	Both
			N	11	Donor	Thr199	O	201	Both
			N	11	Donor	His96	N	94	Acceptor
			N	11	Donor	His94	N	82	Acceptor
			O	9	Acceptor	His119	N	113	Donor
2k	-7.4	6	O	10	Acceptor	Thr199	N	196	Donor
			O	10	Acceptor	Thr199	O	201	Both
			N	11	Donor	Thr199	O	201	Both
			N	11	Donor	His96	N	94	Acceptor
			N	11	Donor	His94	N	82	Acceptor
			O	9	Acceptor	His119	N	113	Donor
2l	-7.0	6	O	11	Acceptor	Thr199	N	196	Donor
			O	11	Acceptor	Thr199	O	201	Both
			N	12	Donor	Thr199	O	201	Both
			N	12	Donor	His96	N	94	Acceptor
			N	12	Donor	His94	N	82	Acceptor
			O	10	Acceptor	His119	N	113	Donor
2m	-6.5	6	O	11	Acceptor	Thr199	N	196	Donor
			O	11	Acceptor	Thr199	O	201	Both
			N	12	Donor	Thr199	O	201	Both
			N	12	Donor	His96	N	94	Acceptor
			N	12	Donor	His94	N	82	Acceptor
			O	10	Acceptor	His119	N	113	Donor
2n	-6.6	7	O	11	Acceptor	Thr199	N	196	Donor
			O	11	Acceptor	Thr199	O	201	Both
			N	12	Donor	Thr199	O	201	Both
			N	12	Donor	His96	N	94	Acceptor
			N	12	Donor	His94	N	82	Acceptor
			O	10	Acceptor	His119	N	113	Donor
			N	25	Donor	Pro201	O	220	Acceptor
2o	-7.0	6	O	10	Acceptor	Thr199	N	196	Donor
			O	10	Acceptor	Thr199	O	201	Both
			N	11	Donor	Thr199	O	201	Both
			N	11	Donor	His96	N	94	Acceptor
			N	11	Donor	His94	N	82	Acceptor
			O	9	Acceptor	His119	N	113	Donor
2p	-6.8	6	O	10	Acceptor	Thr199	N	196	Donor
			O	10	Acceptor	Thr199	O	201	Both
			N	11	Donor	Thr199	O	201	Both
			N	11	Donor	His96	N	94	Acceptor
			N	11	Donor	His94	N	82	Acceptor
			O	9	Acceptor	His119	N	113	Donor
2q	-6.7	5	O	10	Acceptor	Thr199	N	196	Donor
			O	10	Acceptor	Thr199	O	201	Both
			N	11	Donor	Thr199	O	201	Both
			N	11	Donor	His96	N	94	Acceptor
			N	11	Donor	His94	N	82	Acceptor
Zonisamide	-6.3	6	N	14	Donor	Thr199	O	201	Both
			N	14	Donor	His96	N	94	Acceptor
			N	14	Donor	His92	N	82	Acceptor
			O	13	Acceptor	Thr199	O	201	Both
			O	18	Acceptor	Thr199	N	196	Donor
			O	12	Acceptor	His119	N	113	Donor
Acetazolmide	-6.4	5	N	15	Donor	His94	N	82	Acceptor
			N	15	Donor	His96	N	94	Acceptor
			N	15	Donor	Thr199	O	201	Both
			O	14	Acceptor	Thr199	O	201	Both
			O	14	Acceptor	Thr199	N	196	Donor

Tab.4 Docking results of all the compounds with receptor 1AZM

Fig.35 Docked images of designed molecules 1a, 1b, 1c, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p and 2q with 1AZM

Comp.	Molecular formula (MW)	Yield (%)	MP (°C)	Elemental analysis (%): Found (Calculated)				% purity	R_f
Comp.	Molecular formula (MW)	Yield (%)	MP (°C)	C	H	N	S	% purity	R_f
1a	C₁₃H₁₂N₂O₃S (276.056)	68.75	205-208	56.42 (56.50)	3.260 (4.37)	10.13 (10.14)	11.16 (11.60)	98.00	0.42
1b	C₁₅H₁₄N₂O₃S (302.072)	71.92	220-222	59.44 (59.58)	1.922 (4.66)	9.224 (9.26)	10.63 (10.60)	96.55	0.80
1c	C₁₁H₁₀N₂O₃S₂ (282.013)	56.73	210-212	39.89 (46.77)	0.969 (3.56)	8.540 (9.92)	19.16 (22.73)	82.59	0.63
2a	C₁₃H₁₅N₃O₂S (277.088)	88.42	215-217	56.01 (56.30)	4.98 (5.45)	14.05 (15.15)	11.14 (11.56)	97.42	0.39
2b	C₁₄H₁₆N₂O₃S (292.088)	68.22	209-211	56.81 (57.52)	4.99 (5.52)	9.42 (9.58)	10.00 (10.97)	97.16	0.41
2c	C₁₄H₁₆N₂O₃S (292.088)	67.80	184-186	57.05 (57.52)	5.10 (5.52)	9.50 (9.58)	10.88 (10.97)	98.72	0.43
2d	C₁₄H₁₆N₂O₃S (292.088)	62.00	180-182	57.10 (57.52)	5.04 (5.52)	9.48 (9.58)	10.02 (10.97)	97.88	0.49
2e	C₁₃H₁₅N₃O₂S (277.088)	85.88	190-192	56.09 (56.30)	4.93 (5.45)	14.87 (15.15)	11.01 (11.56)	98.23	0.48
2f	C₁₃H₁₅N₃O₂S (277.088)	80.02	185-187	56.02 (56.30)	4.92 (5.45)	15.01 (15.15)	11.32 (11.56)	98.65	0.52
2g	C₁₅H₁₆N₂O₃S (304.088)	82.44	194-197	58.09 (59.19)	5.10 (5.30)	9.17 (9.20)	9.28 (10.54)	96.92	0.45
2h	C₁₄H₁₇N₃O₂S (291.104)	88.33	198-200	56.87 (57.71)	4.98 (5.88)	14.02 (14.42)	10.31 (11.00)	96.82	0.51
2i	C₁₄H₁₇N₃O₂S (291.104)	86.53	200-202	56.76 (57.71)	5.06 (5.88)	13.82 (14.42)	10.32 (11.00)	96.57	0.47
2j	C₁₆H₁₈N₂O₃S (318.103)	61.21	197-200	59.62 (60.36)	4.94 (5.70)	8.13 (8.80)	9.89 (10.07)	97.23	0.58
2k	C₁₆H₁₈N₂O₃S (318.103)	60.54	188-190	60.05 (60.36)	4.38 (5.70)	8.13 (8.80)	9.22 (10.07)	96.29	0.38
2l	C₁₆H₂₁N₃O₂S (319.135)	89.12	204-206	59.01 (60.16)	4.32 (6.63)	11.32 (13.16)	8.98 (10.04)	92.93	0.53
2m	C₁₆H₂₁N₃O₂S (319.135)	86.78	203-205	59.41 (60.16)	5.41 (6.63)	12.33 (13.16)	9.07 (10.04)	95.81	0.33
2n	C₁₆H₂₁N₃O₂S (319.135)	81.89	187-189	58.97 (60.16)	6.41 (6.63)	12.84 (13.16)	9.65 (10.04)	97.64	0.50
2o	C₁₇H₂₂N₂O₃S (334.135)	61.22	206-208	60.22 (61.05)	5.44 (6.63)	7.96 (8.38)	8.95 (9.59)	96.40	0.36
2p	C₁₇H₂₂N₂O₃S (334.135)	60.22	183-185	60.86 (61.05)	5.78 (6.63)	8.02 (8.38)	9.01 (9.59)	97.68	0.40
2q	C₁₇H₂₂N₂O₃S (334.135)	59.35	196-198	57.88 (61.05)	4.53 (6.63)	7.31 (8.38)	8.98 (9.59)	91.88	0.61

Tab.5 Physical and elemental data of all the synthesized compounds

Fig.36

Fig.37

Fig.38

Fig.39

Fig.40

Fig.41

Fig.42

Fig.43

Fig.44

Fig.45

Fig.46

Fig.47

Fig.48

Fig.49

Fig.50

Fig.51

Fig.52

Fig.53

Fig.54

Fig.55

Tab.6 Anticonvulsant (MES) activity and neurotoxicity of synthesized compounds

Tab.7 Anticonvulsant effect on all phases of MES model

Tab.8 Biological activity Spectrum against Carbonic anhydrase (Probability to be active)

Tab.9 Probability and current status to be mutagenic and skin irritant of designed screened compound

Tab.10 Predicted oral rat LD₅₀

Fig.56 Carbonic anhydrase inhibitors.

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