In-silico based Designing of benzo[d]thiazol-2-amine Derivatives as Analgesic and Anti-inflammatory Agents


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Abstract

Background:Benzo[d]thiazoles represent a significant class of heterocyclic com-pounds renowned for their diverse pharmacological activities, including analgesic and anti-inflammatory properties. This molecular scaffold holds substantial interest among medicinal chemists owing to its structural versatility and therapeutic potential. Incorporating the benzo[d]thiazole moiety into drug molecules has been extensively investigated as a strategy to craft novel therapeutics with heightened efficacy and minimized adverse effects.

Aims:The aim of the present research work was to design, synthesize and characterize the new benzo[d]thiazol-2-amine derivatives as potent analgesic and anti-inflammatory agents.

Materials and Methods:The synthesis of the presented benzo[d]thiazol-2-amine derivatives was performed by condensing-(4-chlorobenzylidene) benzo[d]thiazol-2-amine with a number of substituted phenols in the presence of potassium iodide and anhydrous potassium carbonate in dry acetone. IR spectroscopy, 1HNMR spectroscopy, 13CNMR spectroscopy and Mass spectroscopy methods were used to characterize the structural properties of all 13 newly synthesized derivatives. The molecular properties of these newly synthesized derivatives were estimated to study the attributes of drug-like candidates. Benzo[d]thiazol-2-amine derivatives were molecularly docked with selective enzymes COX-1 and COX-2.

:Analgesic and anti-inflammatory activities of synthesized compounds were evaluated by using albino rats.

Results:Findings of the research suggested that compounds G3, G4, G6, G8 and G11 possess higher binding affinity than diclofenac sodium, when docking was performed with enzyme COX-1. Compounds G1, G3, G6, G8 and G10 showed lower binding affinity than Indometh-acin when docking was performed with enzyme COX-2. In vitro evaluation of the COX-1 and COX-2 enzyme inhibitory activities was performed for synthesized compounds.

Discussion:Compounds G10 and G11 exhibited significant COX-1 and COX-2 enzyme in-hibitory action with an IC50 value of 5.0 and 10 µM, respectively. Using the hot plate method and the carrageenan-induced rat paw edema model, the synthesized compounds were screened for their biological activities, including analgesic and anti-inflammatory activities. Highest analgesic action was exhibited by derivative G11 and the compound G10 showed the highest anti-inflammatory response. Inhibition of COX may be considered as a mechanism of action of these compounds.

Conclusion:It was concluded that synthesized derivatives G10 and G11 exhibited significant analgesic and anti-inflammatory effect; therefore, the said compounds may be subjected to further clinical investigation for establishing these as future compounds for the treatment of pain and inflammation.

About the authors

Arun Mishra

Central Facility of Instrumentation, SOS School of Pharmacy, IFTM University

Author for correspondence.
Email: info@benthamscience.net

Kamal Thajudeen

Department of Pharmacognosy, College of Pharmacy, King Khalid University

Email: info@benthamscience.net

Mhaveer Singh

School of Pharmaceutical Sciences, IFTM University

Email: info@benthamscience.net

Gulam Rasool

Drug Design Laboratory, School of Pharmaceutical Sciences, IFTM University

Email: info@benthamscience.net

Arvind Kumar

Drug Design Laboratory, School of Pharmaceutical Sciences, IFTM University

Email: info@benthamscience.net

Harpreet Singh

Drug Design Laboratory, School of Pharmaceutical Sciences, IFTM University

Email: info@benthamscience.net

Kalicharan Sharma

School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences & Research University

Email: info@benthamscience.net

Amrita Mishra

School of Pharmaceutical Sciences, Delhi Pharmaceutical Science and Research University

Email: info@benthamscience.net

References

  1. Waliza, A.; Ghosh, S. Inflammation and inflammatory diseases, markers, and mediators,role of CRP in some inflammatory diseases. Biol. C React. Protein Health Dis., 2016, 1, 67-107.
  2. Arshia, J.A.; Jabeen, A.; Faheem, A.; Khan, K.M.; Shah, S.; Perveen, S. Benzophenone esters and sulfonates: Synthesis and their potential as antiinflammatory agents. Med. Chem., 2019, 15(2), 162-174. doi: 10.2174/1573406414666180806114825 PMID: 30081790
  3. Miller, R.G.; Mitchell, J.D.; Moore, D.H. Riluzole for amyotropic lateral sclerosis/motor neuron disease. Cochrane Database Syst. Rev., 2012, 2, 1-5.
  4. Wongrakpanich, S.; Wongrakpanich, A.; Melhado, K.; Rangaswami, J. A comprehensive review of non-steroidal anti-inflammatory drug use in the elderly. Aging Dis., 2018, 9(1), 143-150. doi: 10.14336/AD.2017.0306 PMID: 29392089
  5. Simmons, D.L.; Botting, R.M.; Hla, T. Cyclooxygenase isozymes: The biology of prostaglandin synthesis and inhibition. Pharmacol. Rev., 2004, 56(3), 387-437. doi: 10.1124/pr.56.3.3 PMID: 15317910
  6. Peskar, B.M. Role of cyclooxygenase isoforms in gastric mucosal defence. J. Physiol. Paris, 2001, 95(1-6), 3-9. doi: 10.1016/S0928-4257(01)00003-1 PMID: 11595412
  7. Zidar, N.; Odar, K.; Glavač, D.; Jerše, M.; Zupanc, T.; Štajer, D. Cyclooxygenase in normal human tissues – is COX‐1 really a constitutive isoform, and COX‐2 an inducible isoform? J. Cell. Mol. Med., 2009, 13(9b), 3753-3763. doi: 10.1111/j.1582-4934.2008.00430.x PMID: 18657230
  8. Wang, B.; Wu, L.; Chen, J.; Dong, L.; Chen, C.; Wen, Z.; Hu, J.; Fleming, I.; Wang, D.W. Metabolism pathways of arachidonic acids: Mechanisms and potential therapeutic targets. Signal Transduct. Target. Ther., 2021, 6(1), 94-99. doi: 10.1038/s41392-020-00443-w PMID: 33637672
  9. Paramashivappa, R.; Phani Kumar, P.; Subba Rao, P.V.; Srinivasa Rao, A. Design, synthesis and biological evaluation of benzimidazole/benzothiazole and benzoxazole derivatives as cyclooxygenase inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(4), 657-660. doi: 10.1016/S0960-894X(02)01006-5 PMID: 12639552
  10. Zhang, X.; Gao, Y.; Wang, Q.; Du, S.; He, X.; Gu, N.; Lu, Y. Riluzole induces LTD of spinal nociceptive signaling via postsynaptic GluR2 receptors. J. Pain Res., 2018, 11, 2577-2586. doi: 10.2147/JPR.S169686 PMID: 30464577
  11. Holman, A.J.; Myers, R.R. A randomized, double‐blind, placebo‐controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum., 2005, 52(8), 2495-2505. doi: 10.1002/art.21191 PMID: 16052595
  12. Kaur, H.; Kumar, S.; Singh, I.; Saxena, K.K.; Kumar, A. Synthesis, characterization and biological activity of substituted benzothiazole derivatives. Dig. J. Nanomater. Biostruct., 2010, 5, 67-76.
  13. Goldstein, J.; Cryer, B. Gastrointestinal injury associated with NSAID use: A case study and review of risk factors and preventative strategies. Drug Healthc. Patient Saf., 2015, 7, 31-41. doi: 10.2147/DHPS.S71976 PMID: 25653559
  14. Hörl, W.H. Nonsteroidal anti-inflammatory drugs and the kidney. Pharmaceuticals, 2010, 3(7), 2291-2321. doi: 10.3390/ph3072291 PMID: 27713354
  15. Zhilitskaya, L.V.; Shainyan, B.A.; Yarosh, N.O. Modern approaches to the synthesis and transformations of practically valuable benzothiazole derivatives. Molecules, 2021, 26(8), 2190. doi: 10.3390/molecules26082190 PMID: 33920281
  16. Ugwu, D.I.; Okoro, U.C.; Ukoha, P.O.; Gupta, A.; Okafor, S.N. Novel anti-inflammatory and analgesic agents: Synthesis, molecular docking and In vivo studies. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 405-415. doi: 10.1080/14756366.2018.1426573 PMID: 29372659
  17. Ikpa, C.B.C.; Onoja, S.O.; Okwaraji, A.O. Synthesis and antibacterial activities of benzothiazole derivatives of sulphonamides. Acta Chemica Malaysia, 2020, 4(2), 55-57. doi: 10.2478/acmy-2020-0009
  18. Haroun, M.; Petrou, A.; Tratrat, C.; Kositsi, K.; Gavalas, A.; Geronikaki, A.; Venugopala, K.N.; Sreeharsha, N. Discovery of benzothiazole-based thiazolidinones as potential anti-inflammatory agents: anti-inflammatory activity, soybean lipoxygenase inhibition effect and molecular docking studies. SAR QSAR Environ. Res., 2022, 33(6), 485-497. doi: 10.1080/1062936X.2022.2084772 PMID: 35703013
  19. Kumar, G.; Singh, N.P. Synthesis, anti-inflammatory and analgesic evaluation of thiazole/oxazole substituted benzothiazole derivatives. Bioorg. Chem., 2021, 107, 104608. doi: 10.1016/j.bioorg.2020.104608 PMID: 33465668
  20. Venugopala, K.N.; Khedr, M.A.; Pillay, M.; Nayak, S.K.; Chandrashekharappa, S.; Aldhubiab, B.E.; Harsha, S.; Attimard, M.; Odhav, B. Benzothiazole analogs as potential anti-TB agents: Computational input and molecular dynamics. J. Biomol. Struct. Dyn., 2019, 37(7), 1830-1842. doi: 10.1080/07391102.2018.1470035 PMID: 29697293
  21. Venugopala, K.N.; Chandrashekharappa, S.; Pillay, M.; Bhandary, S.; Kandeel, M.; Mahomoodally, F.M.; Morsy, M.A.; Chopra, D.; Aldhubiab, B.E.; Attimarad, M.; Alwassil, O.I.; Harsha, S.; Mlisana, K.; Odhav, B. Synthesis and structural elucidation of novel benzothiazole derivatives as anti-tubercular agents: In-silico screening for possible target identification. Med. Chem., 2019, 15(3), 311-326. doi: 10.2174/1573406414666180703121815 PMID: 29968540
  22. Amnerkar, N.D.; Bhusari, K.P. Synthesis of some thiazolyl aminobenzothiazole derivatives as potential antibacterial, antifungal and anthelmintic agents. J. Enzyme Inhib. Med. Chem., 2011, 26(1), 22-28. doi: 10.3109/14756360903555258 PMID: 21250821
  23. Rajareddy, A.; Murthy, M.S. Synthesis, characterization, and anthelmintic activity of novel benzothiazole derivatives containing indole moieties. Asian J. Pharm. Clin. Res., 2019, 12, 321-325. doi: 10.22159/ajpcr.2019.v12i3.30530
  24. Ali, S.; Ali, M.; Khan, A.; Ullah, S.; Waqas, M.; Al-Harrasi, A.; Latif, A.; Ahmad, M.; Saadiq, M. Novel 5-(Arylideneamino)-1 H -Benzo dimidazole-2-thiols as Potent Anti-Diabetic Agents: Synthesis, in vitro α-glucosidase inhibition, and molecular docking studies. ACS Omega, 2022, 7(48), 43468-43479. doi: 10.1021/acsomega.2c03854 PMID: 36506132
  25. Mariappan, G.; Prabhat, P.; Sutharson, L.; Banerjee, J.; Patangia, U.; Nath, S. Synthesis and antidiabetic evaluation of benzothiazole derivatives. J. Korean Chem. Soc., 2012, 56(2), 251-256. doi: 10.5012/jkcs.2012.56.2.251
  26. Azzam, R.A.; Elboshi, H.A.; Elgemeie, G.H. Novel synthesis and antiviral evaluation of new benzothiazole-bearing N -Sulfonamide 2-Pyridone Derivatives as USP7 Enzyme Inhibitors. ACS Omega, 2020, 5(46), 30023-30036. doi: 10.1021/acsomega.0c04424 PMID: 33251438
  27. Djuidje, E.N.; Barbari, R.; Baldisserotto, A.; Durini, E.; Sciabica, S.; Balzarini, J.; Liekens, S.; Vertuani, S.; Manfredini, S. Benzothiazole derivatives as multifunctional antioxidant agents for skin damage: Structure–activity relationship of a scaffold bearing a five-membered ring system. Antioxidants, 2022, 11(2), 407-413. doi: 10.3390/antiox11020407 PMID: 35204288
  28. Irfan, A.; Batool, F.; Zahra Naqvi, S.A.; Islam, A.; Osman, S.M.; Nocentini, A.; Alissa, S.A.; Supuran, C.T.; Supuran, C.T. Benzothiazole derivatives as anticancer agents. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 265-279. doi: 10.1080/14756366.2019.1698036 PMID: 31790602
  29. Alizadeh, S.R.; Hashemi, S.M. Development and therapeutic potential of 2-aminothiazole derivatives in anticancer drug discovery. Med. Chem. Res., 2021, 30(4), 771-806. doi: 10.1007/s00044-020-02686-2 PMID: 33469255
  30. Gagoria, J.; Verma, P.K.; Khatkar, A. Anticonvulsant and neurological profile of benzothiazoles: A mini-review. Cent. Nerv. Syst. Agents Med. Chem., 2015, 15(1), 11-16. doi: 10.2174/1871524915666150112094206 PMID: 25578435
  31. Jin, Q.; Fu, Z.; Guan, L.; Jiang, H. Syntheses of BenzodThiazol-2(3H)-one derivatives and their antidepressant and anticonvulsant effects. Mar. Drugs, 2019, 17(7), 430-436. doi: 10.3390/md17070430 PMID: 31340514
  32. Haroun, M.; Chobe, S.S.; Alavala, R.R.; Mathure, S.M.; Jamullamudi, R.N.; Nerkar, C.K.; Gugulothu, V.K.; Tratrat, C.; Islam, M.M.; Venugopala, K.N.; Habeebuddin, M.; Telsang, M.; Sreeharsha, N.; Anwer, M.K. 1,5-Benzothiazepine Derivatives: Green synthesis, in silico and in vitro evaluation as anticancer agents. Molecules, 2022, 27(12), 3757-3762. doi: 10.3390/molecules27123757 PMID: 35744881
  33. Venugopala, K.N.; Krishnappa, M.; Nayak, S.K.; Subrahmanya, B.K.; Vaderapura, J.P.; Chalannavar, R.K.; Gleiser, R.M.; Odhav, B. Synthesis and antimosquito properties of 2,6-substituted benzodthiazole and 2,4-substituted benzodthiazole analogues against Anopheles arabiensis. Eur. J. Med. Chem., 2013, 65, 295-303. doi: 10.1016/j.ejmech.2013.04.061 PMID: 23727539
  34. Khokra, S.L.; Arora, K.; Khan, S.A.; Kaushik, P.; Saini, R.; Husain, A. Synthesis, computational studies and anticonvulsant activity of novel benzothiazole coupled sulfonamide derivatives. Iran. J. Pharm. Res., 2019, 18(1), 1-15. PMID: 31089339
  35. Haroun, M.; Tratrat, C.; Petrou, A.; Geronikaki, A.; Ivanov, M.; Ćirić, A.; Soković, M.; Nagaraja, S.; Venugopala, K.N.; Balachandran Nair, A.; Elsewedy, H.S.; Kochkar, H. Exploration of the antimicrobial effects of benzothiazolylthiazolidin-4-one and in silico mechanistic investigation. Molecules, 2021, 26(13), 4061-4067. doi: 10.3390/molecules26134061 PMID: 34279400
  36. Karlgren, M.; Bergstrom, C.A.S. How Physicochemical Properties of Drugs Affect Their Metabolism and Clearance. In: New Horizons in Predictive Drug Metabolism and Pharmacokinetics, 49th; The Royal Society of Chemistry, 2016, pp. 1-26.
  37. Mishra, A.K.; Anjali, K.; Singh, H.; Mishra, A.; Kumar, A. Synthesis and in silico studies of some new pyrrolidine derivatives and their biological evaluation for analgesic and anti-inflammatory activity. Ann. Pharm. Fr., 2023, 81(5), 801-813. doi: 10.1016/j.pharma.2023.03.002 PMID: 36931432
  38. Zhao, Y.H.; Abraham, M.H.; Le, J.; Hersey, A.; Luscombe, C.N.; Beck, G.; Sherborne, B.; Cooper, I. Rate-limited steps of human oral absorption and QSAR studies. Pharm. Res., 2002, 19(10), 1446-1457. doi: 10.1023/A:1020444330011 PMID: 12425461
  39. Systemes Dassault. BIOVIA, Discovery Studio Modeling Environment; Dassault SystemesBiovia: San Diego, CA, USA, 2017.
  40. Gedawy, E.M.; Kassab, A.E.; El Kerdawy, A.M. Design, synthesis and biological evaluation of novel pyrazole sulfonamide derivatives as dual COX-2/5-LOX inhibitors. Eur. J. Med. Chem., 2020, 189, 112066-112069. doi: 10.1016/j.ejmech.2020.112066 PMID: 31982653
  41. OECD guidelines for testing of chemicals. Revised Draft Guidelines 423, Acute Oral Toxicity Class Method. 2000. Available from: https://ntp.niehs.nih.gov/sites/default/files/iccvam/suppdocs/feddocs/oecd/oecd_gl423.pdf
  42. Eddy, N.B.; Leimbach, D. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J. Pharmacol. Exp. Ther., 1953, 107(3), 385-393. PMID: 13035677
  43. Yasir, A.; Ishtiaq, S.; Jahangir, M.; Ajaib, M.; Salar, U.; Khan, K.M. Biology-Oriented Synthesis (BIOS) of piperine derivatives and their comparative analgesic and antiinflammatory activities. Med. Chem., 2018, 14(3), 269-280. doi: 10.2174/1573406413666170623083810 PMID: 28641526
  44. Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Exp. Biol. Med., 1962, 111(3), 544-547. doi: 10.3181/00379727-111-27849 PMID: 14001233
  45. Venkatesh, P.; Pandeya, S.N. Synthesis, characterisation and anti-inflammatory activity of some 2-amino benzothiazole derivatives. Int. J. Chemtech Res., 2009, 1, 1354-1358.
  46. Zhilitskaya, L.V.; Yarosh, N.O. Synthesis of biologically active derivatives of 2-aminobenzothiazole. Chem. Heterocycl. Compd., 2021, 57(4), 369-373. doi: 10.1007/s10593-021-02914-6 PMID: 33994555
  47. Kumar, S.; Kumar, A.; Verma, A.; Mishra, A.K.; Mishra, A.K. Synthesis and docking study of some bioactive N-(benzodthiazol-2-yl)- 2-(4-((substituted)phenoxy)acetamide on Cyclo-oxygenase-2 enzyme and In vivo analgesic activity evaluation. Lett. Drug Des. Discov., 2021, 18(4), 396-405. doi: 10.2174/1570180817999201022193901
  48. Deodhar, M.N.; Dongre, A.C.; Kudale, S.D. Analgesic and antiinflammatory activity of derivatives of 2-aminobenzothiazole. Asian J. Chem., 2012, 24, 2747-2752.
  49. Gupta, P.; Yadav, H.L.; Garg, G.; Pawar, R.S.; Patil, U.K.; Singour, U.K. Synthesis and biological evaluation of some novel 2-aminobenzothiazole derivatives as potential analgesic agents. Asian J. Res. Chem, 2010, 3(1), 347-350.
  50. Gill, R.K.; Rawal, R.K.; Bariwal, J. Recent advances in the chemistry and biology of benzothiazoles. Arch. Pharm., 2015, 348(3), 155-178. doi: 10.1002/ardp.201400340
  51. Kumar, K.R.; Karthik, K.N.; Begum, P.R.; Rao, C.M. Synthesis, characteristics and biological evaluation of benzothiazole derivatives as potential antimicrobial and analgesic agents. Asian J. Res. Pharm. Sci., 2017, 28, 115-119.
  52. Siddiqui, N.; Rana, A.; Khan, S.A.; Ahsan, W.; Alam, M.S.; Ahmed, S. Analgesic and antidepressant activities of benzothiazole-benzamides. Biomed. Pharmacol. J., 2008, 1, 297-300.
  53. Cashman, J.N. The mechanisms of action of NSAIDs in analgesia. Drugs, 1996, 52(Suppl. 5), 13-23. doi: 10.2165/00003495-199600525-00004 PMID: 8922554
  54. Habeeb, A.G.; Praveen Rao, P.N.; Knaus, E.E. Design and synthesis of 4,5-diphenyl-4-isoxazolines: Novel inhibitors of cyclooxygenase-2 with analgesic and antiinflammatory activity. J. Med. Chem., 2001, 44(18), 2921-2927. doi: 10.1021/jm0101287 PMID: 11520200
  55. Saify, Z.S.; Khan, K.M.; Haider, S.M.; Zeeshan, S.T.A.; Shah, S.T.A.; Saeed, M.; Shekhani, M.S.; Voelter, W. Syntheses and evaluation of the analgesic activity of some 4-Acetyl- 4-phenylpiperidine and 4-Hydroxy-4-phenylpiperidine derivatives. Z. Naturforsch. B. J. Chem. Sci., 1999, 54(10), 1327-1336. doi: 10.1515/znb-1999-1017

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