Design, Synthesis and Molecular Docking Studies of Novel Thiadiazole Analogues with Potential Antimicrobial and Antiinflammatory Activities

Author(s): Dinesh K. Mehta*, Poonam Taya, Rina Das, Kamal Dua.

Journal Name: Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents)

Volume 18 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Chemical modification of thiadiazole may lead to a potent therapeutic agent. In this study, biological properties of thiadiazole derivatives were evaluated by assessing their antimicrobial and anti-inflammatory activities.

Methods: A series of novel derivatives of N-(5-(1-methyl-indol-3-yl)-1,3,4-thiadiazol-2- yl)-2-(5-substitutedphenyl)-3-(phenylamino)-4,5-dihydropyrazol-1-yl) acetamide have been synthesized and evaluated for their antimicrobial activity. Anti-inflammatory activity was done using carrageenan-induced inflammation in rat paw edema model. In-silico molecular docking studies of the synthesized compounds were performed on crystal structures of Aspergillus niger, Bacillus subtilis, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Cyclooxygenase-2 (obtained from using GRIP batch docking method of V-life MDS 3.0 software. The structures of the newly synthesized compounds were confirmed by FT-IR, 1H-NMR, 13C-NMR and Mass spectroscopy.

Results: Antimicrobial and Anti-inflammatory activity study of the novel synthesized compounds were screened. Synthesized compounds having methoxy substitution on the 3rd and 4th positions of aromatic ring are utmost active amongst all the derivatives. Compounds 6d, 6i, 6j and 6l were found to possess good anti-inflammatory activity having percentage of inhibition to the extent of 46.8%, 48.1%, 49.4%, and 48.5% as compared with Diclofenac.

Conclusion: The experimental results were further supported by molecular docking analysis describing the better interaction patterns.

Keywords: Anti-inflammatory, anticancer, antimicrobial, bacterial infection, in-silico docking, thiadiazole.

Sy, M.; Kitazawa, M.; Medeiros, R.; Whitman, L.; Cheng, D.; Lane, T.E.; Laferla, F.M. Inflammation induced by infection potentiates tau pathological features in transgenic mice. Am. J. Pathol., 2011, 178(6), 2811-2822.
Camoutsis, C.; Geronikaki, A.; Ciric, A.; Soković, M.; Zoumpoulakis, P.; Zervou, M. Sulfonamide-1,2,4-thiadiazole derivatives as antifungal and antibacterial agents: Synthesis, biological evaluation, lipophilicity, and conformational studies. Chem. Pharm. Bull. (Tokyo), 2010, 58(2), 160-167.
Jain, A.K.; Sharma, S.; Vaidya, A.; Ravichandran, V.; Agrawal, R.K. 1,3,4-Thiadiazole and its derivatives: A review on recent progress in biological activities. Chem. Biol. Drug Des., 2013, 81(5), 557-576.
Talapatra, S.K.; Tham, C.L.; Guglielmi, P.; Cirilli, R.; Chandrasekaran, B.; Karpoormath, R.; Carradori, S.; Kozielski, F. Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors. Eur. J. Med. Chem., 2018, 156, 641-651.
Bachwani, M.; Kumar, R. Molecular docking: A review. Int. J. Res. Ayurveda Pharm., 2011, 2(6), 1746-1751.
Katsila, T.; Spyroulias, G.A.; Patrinos, G.P.; Matsoukas, M.T. Computational approaches in target identification and drug discovery. Comput. Struct. Biotechnol. J., 2016, 14, 177-184.
Kushwaha, N.; Kushwaha, S.K.S.; Rai, A.K. Biological activities of thiadiazole derivatives: A review. Int. J. Chemtech Res., 2012, 4(6), 517-531.
Kavitha, C.V.; Basappa, S.; Swamy, S.N.; Mantelingu, K.; Doreswamy, S.; Sridhar, M.A.; Shashidhara Prasad, J.; Rangappa, K.S. Synthesis of new bioactive venlafaxine analogs: Novel thiazolidin-4-ones as antimicrobials. Bioorg. Med. Chem., 2006, 14(7), 2290-2299.
Husain, K.; Abid, M.; Azam, A. Synthesis, characterization and antiamoebic activity of new indole-3-carboxaldehyde thiosemicarbazones and their Pd(II) complexes. Eur. J. Med. Chem., 2007, 42(10), 1300-1308.
Suma, B.V.; Vijayalakshmi, S.; Madhavan, V.; Murali, A. Synthesis and anticonvulsant activities of some novel 1,3,4-thiadiazole derivatives. Med. Chem. Dr. Disc., 2013, 4(2), 100-107.
Sharshira, E.M.; Hamada, N.M.M. Synthesis, characterization and antimicrobial activities of some thiazole derivatives. Amer. J. Org. Chem., 2012, 2(3), 69-73.
Beena, K.P. Akelesh. Design, synthesis, characterization and evaluation of some 1,3-oxazine derivatives as potent antimicrobial agents. Der Pharmacia Letter., 2013, 5(4), 257-260.
Issaca, Y.A.; Mohamed, S.K.; Eissaa, A.E.M.M.F.; Tantawya, A.H.; El-Sawya, A.A. Synthesis of pentadecanyl-amino thiadiazole pharmacophores and their antimicrobial assessments. J. Chem. Pharm. Res., 2012, 4(5), 2744-2750.
Patneedi, C.B.; Prasadu, K.D.; Sharma, R.S.K. Synthesis of heterocyclic chalconoid derivatives. Pharma. Chem., 2015, 7(8), 10-16.
Ghareb, N.; Elshihawy, H.A.; Abdel-Daim, M.M.; Helal, M.A. Novel pyrazoles and pyrazolo[1,2-a]pyridazines as selective COX-2 inhibitors; Ultrasound-assisted synthesis, biological evaluation, and DFT calculations. Bioorg. Med. Chem. Lett., 2017, 27(11), 2377-2383.
Thanh, N.D.; Giang, N.T.K.; Quyen, T.H.; Huong, D.T.; Toan, V.N. Synthesis and evaluation of in vivo antioxidant, in vitro antibacterial, MRSA and antifungal activity of novel substituted isatin N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazones. Eur. J. Med. Chem., 2016, 123, 532-543.
Balouiri, M.; Sadiki, M.; Ibnsouda, S.K. Methods for in vitro evaluating antimicrobial activity: A review. J. Pharm. Anal., 2016, 6(2), 71-79.
Hałasa, R.; Turecka, K.; Orlewska, C.; Werel, W. Comparison of fluorescence optical respirometry and microbroth dilution methods for testing antimicrobial compounds. J. Microbiol. Methods, 2014, 107, 98-105.
Cruickshank, R.; Duguid, J.P.; Marmion, B.P.; Swain, R.H.A. The enterobacteriaceae. Salmonella. Med. Microbiol., 1975, 11, 403-419.
Cristina, A.; Leonte, D.; Vlase, L.; Bencze, C.L.; Imre, S.; Marc, G.; Apan, B.; Mogoșan, C.; Zaharia, V. Heterocycles 48. Synthesis, characterization and biological evaluation of imidazo[2,1-b][1,3,4]thiadiazole derivatives as anti-inflammatory agents. Molecules, 2018, 23(10), 2425.
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc. Soc. Exp. Biol. Med., 1962, 111, 544-547.
Bhati, S.K.; Kumar, A. Synthesis of new substituted azetidinoyl and thiazolidinoyl-1,3,4-thiadiazino (6,5-b) indoles as promising anti-inflammatory agents. Eur. J. Med. Chem., 2008, 43(11), 2323-2330.
Nadenla, R.R. Molecular Modeling: A Powerful Tool for Drug Designand Molecular Docking. Resonance, 2004, 9(5), 51-60.
Malleshappa, N.N.; Patel, H.M. A comparative QSAR analysis and molecular docking studies of quinazoline derivatives as tyrosine kinase (EGFR) inhibitors: A rational approach to anticancer drug design. Saudi J. Chem. Soc., 2013, 17, 361-379.
Bhuva, H.A.; Kini, S.G. Synthesis, anticancer activity and docking of some substituted benzothiazoles as tyrosine kinase inhibitors. J. Mol. Graph. Model., 2010, 29(1), 32-37.
Onkara; Kumar, A.S.; Kanakaraju, S.; Prasanna, B.; Pydisetty, Y. Molecular docking studies, synthesis and anti-bacterial properties of new mannich bases. Int. J. Pharma Bio Sci., 2013, 4(2), 263-270.
Rishipathak, D.; Shirodkar, P. Design and molecular docking studies of some 1,3,4-oxadiazole derivatives. Int. J. Pharm. Sci. Rev. Res., 2013, 23(1), 285-289.
Salman, A.S.; Mahmoud, N.A.; Aziem, A.A.; Mohamed, M.A.; Elsisi, D.M. Synthesis, reactions and antimicrobial activity of some new 3-substituted indole derivatives. Int. J. Org. Chem. (Irvine), 2015, 5, 81-99.
Buvana, C.; Mahalaksmi, A.; Mathew, B.; Sukumar, M. Synthesis of some thiazolidinone derivatives from indole 2-carboxylic acid and evaluation of its xanthine oxidase inhibitory and antioxidant activity. Int. J. Chemtech Res., 2011, 3, 671-675.
Farghaly, A.R. Synthesis of some new indole derivatives containing pyrazoles with potential antitumor activity. ARKIVOC, 2010, 6, 177-187.
Hassan, F.A. Synthesis and biological evaluation of 1,3,4 thiadiazole derivative on some parameters of immunity and liver enzymes. Int. J. Res. Pharm. Chem., 2012, 2(1), 2231-2781.
Hawaiz, F.E.; Samad, M.K. Synthesis and spectroscopic characterization of some new biological active azo-pyrazoline derivatives. Eur. J. Chem., 2012, 9(3), 1613-1622.
Pattan, S.R. kekare, P.; Dighe, N.S.; Nirmal, S.A.; Musmade, D.S.; Parjane, S.K.; Daithankar, A.V. Synthesis and biological evaluation of some 1, 3, 4-thiadiazoles. J. Chem., 2009, 1(1), 191-198.
Ecobichon, D.J. The Basis of Toxicology Testing; CRC Press: New York, 1997, pp. 43-86.
Upmanyu, N.; Gupta, J.K.; Shah, K.; Mishra, P. Anti-inflammatory and antinociceptive evaluation of newly synthesized 4-(substituted ethanoyl) amino-3-mercapto-5-(4-methoxy) phenyl-1,2,4-triazoles. J. Pharm. Bioallied Sci., 2011, 3(2), 259-265.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [91 - 109]
Pages: 19
DOI: 10.2174/1871520619666190307162442
Price: $65

Article Metrics

PDF: 66
PRC: 1