Synthesis, Structural Characterization, and Thermal Stability Investigation of Methoxybenzamide Derivatives Containing the 5-Mercapto-1,3,4-Thiadiazol-2-yl Group

Year 2025, Volume: 2 Issue: 1, 18 - 25, 31.01.2025

Şenol Yavuz , Ersin Demir , Naki Çolak , Dursun Ali Köse

Abstract

Compounds with a methoxy benzamide structure contain a methoxy group (–OCH₃) and an amide functional group (–CONH₂) within a benzene ring. This causes the compound to exhibit a complex structure with polar and nonpolar characteristics. These compounds are significant in pharmaceutical chemistry, biological research, and chemical synthesis. Due to its active properties, the “N–C–S” linkage in the thiazole ring can chelate metal ions. The antimicrobial activity of benzamide compounds derived from thiazoles and their wide applications in medicine increases the importance of methoxybenzamide derivetives. In this study, 5-amino-1,3,4-thiadiazole-2-thiol compounds were reacted with 2-methoxy, 3-methoxy, and 4-methoxybenzoyl chloride in toluene under a reflux condenser, resulting in the synthesis of methoxybenzamide derivatives (a, b, c). The structural characterization of the obtained methoxybenzamide (a, b, c) compounds were performed using FTIR, LC/MS-ESI, 1H NMR, 13C APT spectroscopy, and elemental analysis. Additionally, the thermal stability of the synthesized methoxybenzamide compounds was investigated through thermal analysis (TGA/DTA/DrTG).

Keywords

Methoxybenzamide, 1, 3, 4-thiadiazol, Synthesis, Structural Characterization, Thermal Stability

References

• 1. Prabukanthan P, Raveendiran C, Harichandran G, Seenuvasakumaran P. Synthesis, crystal growth, crystal structure, optical, thermal, biological and NLO studies of heterocyclic compound N-(1, 3-benzothiazol-2-yl)- 2-methoxybenzamide. Results Chem. 2020;2:100083. doi:10.1016/j.rechem.2020.100083.
• 2. Wang L, Wang DH, Zhang GH, Xu D, Deng WX. Crystal structure, spectroscopic investigation and thermal properties of L-lysine p-toluenesulfonate. J Mol Struct. 2016;1108:179-186. doi:10.1016/j. molstruc.2015.11.019.
• 3. Mermer A, Bayrak H, Alyar S, Alagumuthu M. Synthesis, DFT calculations, biological investigation, molecular docking studies of β-lactam derivatives. J Mol Struct. 2020;1208:127891. doi:10.1016/j.molstruc.2020.127891.
• 4. John JS, Sajan D, Prabukanthan P, Philip R, Joy N. Enhanced NLO activity of organic 2-methyl-5-nitroaniline crystal: Experimental and computational investigation with and without silver addition. Opt Laser Technol. 2019;113:416-427. doi:10.1016/j. optlastec.2019.01.014.
• 5. Shkir M, Abbas H. Physico-chemical properties of L-asparagine L-tartaric acid single crystals: A new nonlinear optical material. Spectrochim Acta Part A Mol Biomol Spectrosc. 2014;118:172- 176. doi:10.1016/j.saa.2013.08.086.
• 6. Prabukanthan P, Lakshmi R, Harichandran G, Sudarsana Kumar C. Synthesis, structural, optical and thermal properties of N-methyl N-aryl benzamide organic single crystals grown bya slow evaporation technique. J Mol Struct. 2018;1156:62-73. doi:10.1016/j.molstruc.2017.11.075.
• 7. Faizi MSH, Osório FAP, Valverde C. Synthesis, crystal structure, spectroscopic and nonlinear optical properties of organic salt: a combined experimental and theoretical study. J Mol Struct. 2020;1210:128039. doi:10.1016/j.molstruc.2020.128039.
• 8. Liu J, Zhou H, Lian Y, Feng Y, Fan T, Xu J, Xu X. Electrically controlled growths of 4-N,N-dimethylamino-40-N0 -methylstilbazolium tosylate (DAST) organic microcrystals. Appl Phys A. 2020;126(3). doi:10.1007/s00339-020-3424-9.
• 9. Liu H, Li M, Wang P, Hu Z, Yin H. Numerical simulation of the flow and mass transport during the growth of ADP crystals by additional stirrer. J Cryst Growth. 2020;534:125507. doi:10.1016/j. jcrysgro.2020.125507.
• 10. Ningaiah S, Bhadraiah UK, Sobha A, Shridevi D. Synthesis of novel pyrazolyl-1,3,4-thiadiazole analogues. Polycyclic Aromatic Compounds. 2020;42(4):1249-1259. doi:10.1080/10406638.202 0.1773875.
• 11. Li M, Zhao B. Progress of the synthesis of condensed pyrazole derivatives (from 2010 to mid-2013). Eur J Med Chem. 2014;85:311-340.
• 12. Radwan A, Khalid M, Amer H, Alotaibi M. Anticancer and molecular docking studies of some new pyrazole-1- carbothioamide nucleosides. Biointerface Res Appl Chem. 2019;9:4642-4648.
• 13. Ehab M, Gedawy AE, Kassab AM, El K. Design, synthesis and biological evaluation of novel pyrazole sulfonamide derivatives as dual COX-2/5-LOX inhibitors. Eur J Med Chem. 2020;189:112066.
• 14. Vijesh AM, Isloor AM, Shetty P, Sundershan S, Fun HK. New pyrazole derivatives containing 1,2,4-triazoles and benzoxazoles as potent antimicrobial and analgesic agents. Eur J Med Chem. 2013;62:410-415.
• 15. Neidiane R, Trindade PR, Lopes LM, Naves JO, Fajemiroye PH, Alves NO, Amaral LM, Liao ACS, Rebelo CH, Castro VA, et al. The newly synthesized pyrazole derivative 5-(1-(3-fluorophenyl)- 1H-pyrazol-4-yl)-2H-tetrazole reduces blood pressure of spontaneously hypertensive rats via NO/cGMO pathway. Front Physiol. 2018;9:1073-1083.
• 16. Malvar DC, Ferreira RT, de Castro RA, de Castro LL, Freitas AC, Costa EA, Florentino IF, Mafra JC, de Souza GE, Vanderlinde FA. Antinociceptive, anti-inflammatory and antipyretic effects of 1.5-diphenyl-1H-pyrazole-3-carbohydrazide, a new heterocyclic pyrazole derivative. Life Sci. 2014;95(2):81-88.
• 17. Reddy GM, Jarem RG, Grigory VZ, Gundala S, Reddy NB. Pyranopyrazoles as efficient antimicrobial agents: Green, one pot and multicomponent approach. Bioorg Chem. 2019;82:324- 331.
• 18. Silva VLM, Elguero J, Silva AMS. Current progress on antioxidants incorporating the pyrazole core. Eur J Med Chem. 2018;156:394- 429.
• 19. Ansari A, Ali A, Asif M, Shamsuzzaman S. Biologically active pyrazole derivatives. New J Chem. 2017;41(1):16-41.
• 20. Satish G, Srinivasa RA, Jeevan LP, Rajeswar RV, Santhosh P. An efficient synthesis of pyrazolyl-1,2,3-thiadiazoles via Hurd–Mori reaction. J Heterocycl Chem. 2019;56:2163-2169.
• 21. Serban G, Stanasel O, Serban E, Bota S. 2-Amino-1,3,4- thiadiazole as a potential scaffold for promising antimicrobial agents. Drug Des Devel Ther. 2018;12:1545-1566.
• 22. Serban G. Synthetic compounds with 2-amino-1,3,4-thiadiazole moiety against viral infections. Molecules. 2020;25(4):942-964.
• 23. Farghaly TA, Abdallah MA, Masaret GS, Muhammad ZA. New and efficient approach for synthesis of novel bioactive [1,3,4] thiadiazoles incorporated with 1,3-thiazole moiety. Eur J Med Chem. 2015;97:320-333.
• 24. Chidananda N, Poojary B, Sumangala V, Kumari NS, Shetty P, Arulmoli T. Facile synthesis, characterization and pharmacological activities of 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles and 5,6-dihydro-3,6- disubstituted-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles. Eur J MedChem. 2012;51:124-136.
• 25. Oruc EE, Rollas S, Kandemirli F, Shvets N, Dimoglo AS. 1,3,4-thiadiazole derivatives. Synthesis, structure elucidation, and structure-antituberculosis activity relationship investigation. J Med Chem. 2004;47(27):6760-6767.
• 26. Megally ANY, Kamel MM. Synthesis and anticancer evaluation of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and Mannich bases. Chem Pharm Bull. 2015;63(5):369-376.
• 27. Dawood KM, Farghaly TA. Thiadiazole inhibitors: A patent review. Expert Opin Ther Patents. 2017;27:477-505. Serban G. Future prospects in the treatment of parasitic diseases: 2-amino-1,3,4-thiadiazoles in leishmaniasis. Molecules. 2019;24:1557.
• 28. Brunton L, Chabner B, Knollman BG. Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill; 2010.
• 29. Pattabiraman VR, Bode JW. Rethinking amide bond synthesis. Nature. 2011;480:471-479.
• 30. Kaspar AA, Reichert JM. Drug future directions for peptide therapeutics development. Discov Today. 2013;18:807-817.
• 31. Brown DG, Bostrom J. Analysis of past and present synthetic methodologies on medicinal chemistry: Where have all the new reactions gone? J Med Chem. 2016;59:4443-4458.
• 32. Ragavan RV, Vijayakumar V, Suchetha Kumari N. Synthesis and antimicrobial activities of novel 1,5-diaryl pyrazoles. Eur J Med Chem. 2010;45(3):1173-1180.
• 33. Ines V, Andrea PR, Kata MM, Karmen B, Branimir B. Synthesis and biological validation of novel pyrazole derivatives with anticancer activity guided by 3D-QSAR analysis. Bioorg Med Chem. 2012;20:2101-2110.
• 34. Rai NP, Narayanaswamy VK, Shashikanth S, Arunachalam PN. Synthesis, characterization and antibacterial activity of 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]- 5-(substituted-phenyl)-[1,3,4]oxadiazoles. Eur J Med Chem. 2009;44(11):4522-4527.
• 35. Vijesh AM, Isloor AM, Shetty P, Sundershan S, Fun HK. New pyrazole derivatives containing 1,2,4-triazoles and benzoxazoles as potent antimicrobial and analgesic agents. Eur J Med Chem. 2013;62:410-415.
• 36. Bekhit AA, Ashour HMA, Ghany YSA, Bekhit AED, Baraka A. Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur J Med Chem. 2008;43(3):456-463.
• 37. Kasımogulları R, Bülbül M, Arslan BS, Gökçe B. Synthesis, characterization and antiglaucoma activity of some novel pyrazole derivatives of 5-amino-1,3,4-thiadiazole-2- sulfonamide. Eur J Med Chem. 2010;45(11):4769-4773.
• 38. Perea S, Patterson TF. Clin Infect Dis. 2002;35:1073.
• 39. Chakrabarti A. Regional Health Forum. 2011;15:97.
• 40. Tscherner M, Schwarzmüller T, Kuchler K. Pharmaceuticals. 2011;4:169.
• 41. White MA, Marr KA, Bowden RA. Clin Microbiol Rev. 1998;11:382.
• 42. Ghannoum MA, Rice LB. Clin Microbiol Rev. 1999;12:501.
• 43. Matysiak J, Niewiadomy A, Krajewska-Kułak E, Ma˛cik- Niewiadomy G. Il Farmaco. 2003;58:455.
• 44. Malik MA, Al-Thabaiti SA, Malik MA. Int J Mol Sci. 2012;13:10880.
• 45. Altıntop MD, Özdemir A, Turan-Zitouni G, Ilgın S, Atlı Ö, Iscan G, Kaplancıklı ZA. Eur J Med Chem. 2012;58:299.
• 46. Tyrkov AG, Abdel’rakhim MA, Sukhenko LT, Degtyarev OV. Pharm Chem J. 2014;47:589.
• 47. Altıntop MD, Kaplancıklı ZA, Çiftçi GA, Demirel R. Eur J Med Chem. 2014;74:264.
• 48. Vembu S, Pazhamalai S, Gopalakrishnan M. Med Chem Res. 2016. Available from: http://dx.doi.org/10.1007/s00044-016-1627-6.
• 49. Kategaonkar AH, Pokalwar RU, Sonar SS, Gawali VU, Shingate BB, Shingare MS. Eur J Med Chem. 2010;45:1128.
• 50. Kategaonkar AH, Labade VB, Shinde PV, Kategaonkar AH, Shingate BB, Shingare MS. Monatsh Chem. 2010;141:787.
• 51. Shashikumar ND, Krishnamurthy G, Bhojyanaik HS, Lokesh MR, Jithendrakumara KS. J Chem Sci. 2014;126:205.
• 52. Łukowska-Chojnacka E, Mierzejewska J, Milner-Krawczyk M, Bondaryk M, Staniszewska M. Synthesis of novel tetrazole derivatives and evaluation of their antifungal activity. Bioorg Med Chem. 2016;24:6058-6065. doi:10.1016/j.bmc.2016.09.066.
• 53. Çolak N, Şahin F, Erten G, Muhammet SM. Synthesis, Structural Analysis, Antimicrobial Activity and The Molecular Electrostatic Potential Surface (MEP) of 2/3/4-Chloro BenzamideSpiro[Benzo[B]Thiophene-Dioxolane] Derivatives. Süleyman Demirel University Faculty of Arts and Sciences Journal of Science. 2024;19(1):53-62.
• 54. Serdaroğlu G, Uludag N, Colak N, Rajkumar P. Nitrobenzamido substitution on thiophene-3-carboxylate: Electrochemical investigation, antioxidant activity, molecular docking, DFT calculations. J Mol Struct. 2023;1271:134030.