Carbonic anhydrase inhibitors with effective anticonvulsant action
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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
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Carbonic anhydrase inhibitors with effective anticonvulsant action
- 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 14
- 15. 15