1) The document describes the design, synthesis, and evaluation of novel benzenesulfonamide derivatives as carbonic anhydrase inhibitors for the treatment of epilepsy. 2) Compounds 15, 16, and 26 were identified as the most potent inhibitors of carbonic anhydrases II and VII and showed effective anticonvulsant activity in animal models of seizures. 3) Of these, Compound 26 displayed the best profile with anticonvulsant action at a low dose of 30 mg/kg, long duration of action up to 6 hours, and oral efficacy in reducing seizure activity. Thus, Compound 26 is identified as a promising carbonic anhydrase inhibitor with anticonv

1. Design, Synthesis, and Pharmacological Evaluation
of Benzenesulfonamide Derivatives as Carbonic
Anhydrase Inhibitors with Effective Anticonvulsant
Action
1
Dushyant Kumar Dewangan
M.S. (Pharm.) Medicinal Chemistry
ID- 427/MS-MC /2017
Department of Medicinal Chemistry
NIPER, Raebareli
26th April 2018

2.  Epilepsy is a complex brain disorder that affects people of all ages and is
characterized by recurrent, unprovoked seizure episodes in affected
persons.
 It is a multifactorial neurological disorder in which numerous receptors,
neurotransmitters, enzymes, and ion channels are engaged in generating
epileptic symptoms.
Approximately 50 million people worldwide have epilepsy, making it one of
the most common neurological diseases globally.
About 10 million persons with epilepsy are there in India.
WHAT IS EPILEPSY ?
2
Tiwari manisha et.al J. Med. Chem. 2018, 61, 3151−3165
https://www.ncbi.nlm.nih.gov/pubmed/24791085 accessed on 25/4/18

3. CARBONIC ANHYDRASE INHIBITORS (CAs) IN EPILEPSY
 As brain CAs are also actively involved to generate seizure episodes and are
attractive targets to handle epileptic seizures.
 Also, It is well studied that neuronal HCO3− influences the excitation of GABAA
which is actively regulated by cytosolic CAs. Especially, isoforms CA II and CA VII are
involved in neuronal pH regulation and have shown a well-defined role in seizure
generation.
 Thus, CAs are promising targets to control seizures as some of the clinically,
successful antiepileptic drugs (AEDs) have shown effective CA inhibitory activity.
3
https://www.slideshare.net/Madison
Brenamen/epilepsy-case-study

4. Clinically used CA Inhibitors with antiepileptic activity
4

5. Designed novel CA Inhibitors
BENZENESULPHONAMIDES
Acetamide Linkers
2-(4-substituted piperazin-yl)-N-(4-sulfamoylbenzyl)acetamides
Propanamide Linkers
3-(4-substituted piperazin-yl)-N-(4-sulfamoylbenzyl)propanamides
Enhanced
Flexibility
5

6. NOVEL BENZENESULPHONAMIDE DERIVATIVE
6

7. SYNTHESIS (Scheme-1)
Compound
No;
R-Group
4
5
6
7
8
9
10
Compound
No;
R-Group
11
12
13
14
15
16
Reagents and Conditions
(A) 30% NaOH,double distilled
H2O, diethyl ether, rt,5h
(B) Substituted piprazines,
Na2CO3, dry DMF, reflux
(80-100), 8-12 h
With Acetamide Linkers
7

8. SYNTHESIS (Scheme-2)
Compound
No;
R-Group
19
20
21
22
23
Compound
No;
R-Group
24
25
26
27
28
Reagents and Conditions
(A) 30% NaOH,double distilled
H2O, diethyl ether, rt,5h
(B) Substituted piprazines,
Na2CO3, dry MeCN, reflux
(80-100), 18-20 h
With Propanamide Linkers
8

9. 9
Compounds
Ki (nM)
hCA II
Inhibitory Action
Ki (nM)
hCA VII
Inhibitory Action
4 94.7 - 244.4
Medium
5 234.5 - 515.2
6 165.2 - 83.9 Reasonable
7 333.1 - 426.8
Medium
8 90.3 Effective 451.9
9 171.6 - 403.9
10 83.9 Satisfactory 396.9
11 75.5 Better 547.4
12 96.7 Satisfactory 296.9
13 203.5 - 171.3
14 384.4 Medium 271.5
15 90.9 Satisfactory 56.9
Reasonable
16 80.4 Better 27.1
AAZ 12.1 Control 2.50 Control
Inhibition of hCA II and hCA VII with Acetamide series Compounds

10. 10
Inhibition of hCA II and hCA VII with Propanamide series Compounds
Compound
Ki (nM)
hCA II
Inhibtory Action
Ki (nM)
hCA VII
Inhibitory
Action
19 120.3 - 89.6 Effective
20 69.9 Good 514.9
Medium
21 252.1
Medium
604.2
22 461.7 61.3 Effective
23 252.5 356.1
Medium
24 60.7 Good 170.1
25 55.8 - 314.6
26 33.2 Better 337.2
27 212.7
Medium
672.3
28 268.4 578.5
AAZ 12.1 Control 2.5 Control

11. MES Screen scPTZ Screen
Compound (dose in mg/kg) 0.5 h 3.0 h 0.5 h 3.0 h
15 (30) 3/6 4/6 2/6 3/6
15 (100) 3/6 5/6 3/6 3/6
16 (30) 1/6 4/6 4/6 1/6
16 (100) 4/6 2/6 3/6 2/6
26 (30) 4/6 4/6 5/6 4/6
26 (100) 5/6 4/6 3/6 3/6
Topiramate (30) 8/8 8/8 3/6 3/6
Topiramate (100) NT NT 2/6 3/6
Acetazolamide (30) 7/8 4/8 3/6 3/6
Acetazolamide (100) 8/8 4/8 5/6 3/6
In-vivo Anticonvulsant Activity of Compounds 15, 16, and 26 in MES and sc-PTZ Seizure Test
11

12. Time MES Test % Protection
0.25 1/6 17
0.5 3/6 50
1 4/6 67
2 4/6 67
3 3/6 50
Anti-MES Activity of Compound 26 (30 mg/kg,bwt) after Oral Administration
Time-Course Anticonvulsant activity of compound 26 (30mg/kg, Ip) in the MES Test
Time (h) MES Test %Protection
0.5 7/10 70
1 8/10 80
2 6/10 60
3 7/10 70
4 7/10 70
6 5/10 50
12

13. CONCLUSION
• Among all, compounds 15, 16, and 26 were the most potent hCA II and hCA VII
inhibitors. These three derivatives displayed effective anticonvulsant activity
against MES as well as sc-PTZ induced seizures.
• Among these three, compounds 26 has –
•excellent antiseizure action in lower dose (30 mg/kg).
•long duration of action and, effective up to 6 h after administration.
•Orally active and has abolished MES stimulated seizures in male Wistar
rats.
• Thus, novel benzenesulfonamide Compound 26 has emerged as a safe and effective
CA inhibitor, which also possesses valuable anticonvulsant action.
13
Compound 26

14. ACKNOWLEDGEMENT
 Dr. S.J.S Flora , Director
 Dr. Atul Kumar , Dean & Course co-ordinator
 Dr. Nihar Ranjan , Asst Professor
 Dr. Abha Sharma , Asst Professor
 Dr. K.N Tiwari , Asst Professor
 Department of Pharmaceuticals, Ministry of chemicals and fertilizers
Govt. of India
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