Medicinal Chemistry Research

, Volume 26, Issue 10, pp 2272–2292 | Cite as

Computational evaluation of 2-amino-5-sulphonamido-1,3,4-thiadiazoles as human carbonic anhydrase-IX inhibitors: an insight into the structural requirement for the anticancer activity against HEK 293

  • Mahavir Chhajed
  • Anil K. Shrivastava
  • Atika Chhajed
  • Vijay Taile
  • Sumeet Prachand
  • Sanjay Jain
Original Research


Carbonic anhydrase inhibitors are very interesting target for designing anticancer agents. A computational procedure was performed on some thiadiazoles derived from carbonic anhydrase inhibitor acetazolamide. Two important procedures in computational drug discovery, namely docking for modeling ligand–receptor interactions and quantitative structure–activity relationships were employed. The relationship between cytotoxic activity and various descriptors was established by stepwise multiple regression analysis. The analyses have produced well predictive and statistically significant quantitative structure–activity relationships models, which were further cross validated. Among several models, one model has good statistical significance (r = 0.89, F test = 6.88, S = 0.33, chance correlation < 0.01), indicates that steric descriptors like EleE are contributing positively to the biological activity, electronic descriptors like connolly molecular surface area and Chi descriptors like chi0 and information theory index like IdAvg are contributing negatively to the biological activity and play a significant role in receptor binding which helps to design some expectedly potent compounds. In order to confirm the obtained results through this ligand-based method, docking was performed on the selected compounds by the use of Schrödinger GLIDE program. Incorporating available biochemical and computational data to the model by correcting the conformation of a single residue lining the binding pocket resulted in significantly improved docking poses. The molecular modeling study allowed confirming the preferential binding mode of reported compounds inside the active site.


Cytotoxicity GLIDE Molecular docking QSAR Thiadiazole 



The authors are thankful to the Principal, RC Patel College of Pharmacy, Shirpur and the HOD, School of Pharmacy, DAVV, Indore for providing facilities to complete this work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1929_MOESM1_ESM.doc (52 kb)
Supplementary Information


  1. Abrahum DJ (2003) Burger’s medicinal chemistry and drug discovery: principle and practice, vol 1, 6th edn. Wiley Interscience, New York, NYCrossRefGoogle Scholar
  2. Alterioa V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S, Scaloni A, Pastorek J, Pastorekova S, Pedone C, Scozzafava A, Montia SM, De Simone G (2009) Crystal structure of the catalytic domain of the tumor associated human carbonic anhydrase IX. Proc Natl Acad Sci USA 106:16233–16238CrossRefGoogle Scholar
  3. Ashida S, Nishimori I, Tanimura M, Onishi S, Shuin T (2002) Effects of von Hippel–Lindau gene mutation and methylation status on expression of transmembrane carbonic anhydrases in renal cell carcinoma. J Cancer Res Clin Oncol 128(10):561–568CrossRefPubMedGoogle Scholar
  4. Brzozowski Z, Slawinski J, Saczewski F, Innocenti A, Supuran CT (2010) Carbonic anhydrase inhibitors: synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with 4-substituted 3-pyridinesulfonamides. Eur J Med Chem 45:2396–2404CrossRefPubMedGoogle Scholar
  5. Cecchi A, Hulikova A, Pastorek J, Pastorekova S, Scozzafava A, Winum JY, Montero JL, Supuran CT (2005) Carbonic anhydrase inhibitors. Design of fluorescent sulfonamides as probes of tumour-associated carbonic anhydrase IX that inhibit isozyme IX-mediated acidification of hypoxic tumours. J Med Chem 48(15):4834–4841CrossRefPubMedGoogle Scholar
  6. Chegwidden WR, Spencer IM, Supuran CT (2001) The roles of carbonic anhydrase in cancer. In: Xue G, Xue Y, Xu Z, Hammond GL, Lim AH (ed) Gene families: studies of DNA, RNA, enzymes, and proteins. World Scientific, Singapore, p 157–169CrossRefGoogle Scholar
  7. Chhajed MR, Khedekar PB, Mundhey AS (2007) Synthesis and free radical scavenging activity of some 1,3,4-thiazole derivatives. Indian J Heterocycl Chem 16:259–262Google Scholar
  8. Chhajed MR, Shrivastava AK, Taile VS (2013) Design and syntheses of some new 5-[benzene sulphonamido]-1,3,4-thiadiazol-2-sulphonamide as potent antiepileptic agent. Macroheterocycles 6(2):199–209. doi: 10.6060/mhc130116c CrossRefGoogle Scholar
  9. Chhajed MR, Shrivastava AK, Taile VS (2014) Synthesis of 5-arylidine amino-1,3,4-thiadiazol-2-[(N-substituted benzyol)]sulphonamides endowed with potent antioxidants and anticancer activity induces growth inhibition in HEK293, BT474 and NCI-H226 cells. Med Chem Res 23:3049–3064. doi: 10.1007/s00044-013-0890-z CrossRefPubMedGoogle Scholar
  10. Chandrabose S, Tripathi SK, Reddy KK, Singh SK (2011) Tool development for prediction of pIC50 values—a pIC50 values from the IC50 value calculator. Curr Trends Biotechnol Pharm 5(2):1104–1109Google Scholar
  11. Chen IJ, Foloppe NJ (2010) Drug-like bioactive structures and conformational coverage with the LigPrep/ConfGen suite: comparison to programs MOE and catalyst. J Chem Inf Model 50(5):822–839CrossRefPubMedGoogle Scholar
  12. Cohen P (2002) Protein kinases—the major drug targets of the twenty-first century? Nat Rev Drug Discov 1:309–315CrossRefPubMedGoogle Scholar
  13. Desai NC, Shukla HK, Astik RR, Thaker KA (1984) Studies on some thiosemicarbazones and 1,3,4-thiadiazolines as potential antitubercular and antibacterial agents. J Indian Chem Soc LXI:168–196Google Scholar
  14. Enkvist E, Lavogina D, Raidaru G, Vaasa A, Viil I, Lust M, Viht K, Uri A (2006) Conjugation of adenosine and hexa-(d-arginine) leads to a nanomolar bisubstrate-analog inhibitor of basophilic protein kinases. J Med Chem 49:7150–7159CrossRefPubMedGoogle Scholar
  15. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47(7):1739–1749CrossRefPubMedGoogle Scholar
  16. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein–ligand complexes. J Med Chem 49:6177–6196CrossRefPubMedGoogle Scholar
  17. Fujikawa-Adachi K, Nishimori I, Taguchi T, Onishi S (1999) Human carbonic anhydrase XIV (CA14): cDNA cloning, mRNA expression, and mapping to chromosome 1. Genomics 61(1):74–81CrossRefPubMedGoogle Scholar
  18. Gill AL, Verdonk M, Boyle RG, Taylor R (2007) A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem 7(14):1408–1422CrossRefPubMedGoogle Scholar
  19. Gupta A, Mishra P, Kashaw SK, Jatav V, Stables JP (2008) Synthesis of 3-aryl amino/amino-4-aryl-5-imino-D2-1,2,4-thiadiazoline and evaluated for anticonvulsant activity. Eur J Med Chem 43(4):749–754CrossRefPubMedGoogle Scholar
  20. Gupta AK, Arockia BM, Kaskhedikar SG (2004) VALSTAT: validation program for quantitative structure activity relationship studies. Indian J Pharm Sci 66:396–402Google Scholar
  21. Hansch C, Leo A (1979) Substituent constants for correlation analysis in chemistry and biology. Wiley, New York, NYGoogle Scholar
  22. Hanna MA, Girges MM, Rasala D, Gawinecki R (1995) Synthesis and pharmacological evaluation of some novel 5-(pyrazol-3-yl)-thiadiazole and oxadiazole derivatives as potential hypoglycemic agents. Arzneim-Forsch Drug Res 45(10):1074–1078Google Scholar
  23. Hilvo M, Baranauskiene L, Salzano MA, Scaloni A, Matulis D, Innocenti A, Scozzafava A, Monti SM, Di Fiore A, De Simone G, Lindfors M, Jänis J, Valjakka J, Pastoreková S, Pastorek J, Kulomaa MS, Nordlund HR, Supuran CT, Parkkila S (2008) Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes. J Biol Chem 283:27799–27809CrossRefPubMedGoogle Scholar
  24. Jain A, Chaturvedi SC (2009) QSAR study on 6-substituted benzimidazoles: an insight into the structural requirement for the angiotensin II AT1 receptor antagonist. Sci Pharm 77:555–565CrossRefGoogle Scholar
  25. Jatav V, Mishra P, Kashaw S, Stables JP (2008) CNS depressant and anticonvulsant activities of some novel 3-[5-substituted-1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. Eur J Med Chem 43(9):1945–1954CrossRefPubMedGoogle Scholar
  26. Kamb A (2005) Opinion: what’s wrong with our cancer models? Nat Rev Drug Discov 4(2):161–165CrossRefPubMedGoogle Scholar
  27. Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) Evaluation and reparametrization of the OPLS-AA force field for protein via comparison with accurate quantum chemical calculations on peptides. J Phys Chem B 105:6474–6477CrossRefGoogle Scholar
  28. Kaunisto K, Parkkila S, Rajaniemi H, WaheedA, Grubb J, Sly WS (2002) Carbonic anhydrase XIV: luminal expression suggests key role in renal acidification. Kidney Int 61(6):2111–2118CrossRefPubMedGoogle Scholar
  29. Kleandrova VV, Speck Planche A (2017) Multitasking model for computer-aided design and virtual screening of compounds with high anti-HIV activity and desirable ADMET properties. In: Speck-Planche A (ed) Multi-scale approaches in drug discovery: from empirical knowledge to in silico experiments and back, 1st edn. Elsevier, Oxford, p 55–81CrossRefGoogle Scholar
  30. Krissinel E, Henrick K (2007) Inference of macromolecular assemblies from crystalline state. J Mol Biol 372:774–797CrossRefPubMedGoogle Scholar
  31. Kumar A, Shrivastava VK, Archana (2003) Synthesis of newer indolyl thiadiazoles and their thiazolidinones and formazans as potential anticonvulsant agents. Indian J Pharm Sci 65(4):358–362Google Scholar
  32. Kumar D, Maruthi Kumar N, Chang KH, Shah K (2010) Synthesis and anticancer activity of 5-(3-indolyl)-1,3,4-thiadiazoles. Eur J Med Chem 45(10):4664–4668CrossRefPubMedGoogle Scholar
  33. Laskowski RA, Hutchinson EG, Michie AD, Wallace AC, Jones ML, Thornton JM (1997) PDBsum: a web-based database of summaries and analyses of all PDB structures. Trends Biochem Sci 22:488–490CrossRefPubMedGoogle Scholar
  34. Lin X, Murray JM, Rico AC, Wang MX, Chu DT, Zhou Y, Del Rosario M, Kaufman S, Ma S, Fang E, Crawford K, Jefferson AB (2006) Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: synthesis and SAR studies. Bioorg Med Chem Lett 16:4163–4168CrossRefPubMedGoogle Scholar
  35. Luan F, Cordeiro MNDS, Alonso N, Garcia-Mera X, Caamano O, Romero-Duran FJ, Yanez M, Gonzalez-Diaz H (2013) TOPS-MODE model of multiplexing neuroprotective effects of drugs and experimental-theoretic study of new 1,3-rasagiline derivatives potentially useful in neurodegenerative diseases. Bioorg Med Chem 21(7):1870–1879CrossRefPubMedGoogle Scholar
  36. Manoharan P, Vijayan RSK, Ghoshal N (2010) Rationalizing fragment based drug discovery for BACE1: insights from FB-QSAR, FB-QSSR, multi objective (MO-QSPR) and MIF studies. J Comput Aided Mol Des 24(10):843–864CrossRefPubMedGoogle Scholar
  37. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592CrossRefPubMedGoogle Scholar
  38. Nam NH, Lee S, Ye G, Sun G, Parang K (2004) ATP-phosphopeptide conjugates as inhibitors of Src tyrosine kinases. Bioorg Med Chem 12:5753–5766CrossRefPubMedGoogle Scholar
  39. Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: insights into drug design from structure. Science 303:1800–1805. doi: 10.1126/science.1095920 CrossRefPubMedGoogle Scholar
  40. Noolvi MN, Patel HM, Singh N, Gadad AK, Cameotra SS, Badiger A (2011) Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b][1,3,4]-thiadiazole derivatives. Eur J Med Chem 46(9):4411–4418CrossRefPubMedGoogle Scholar
  41. Oruc EE, Rollas S, Kandemirli F, Shvets N, Dimoglo AS (2004) 1,3,4-Thiadiazole derivatives. Synthesis, structure elucidation, and structure-antituberculosis activity relationship investigation. J Med Chem 47:6760–6767CrossRefPubMedGoogle Scholar
  42. Pastorekova S, Parkkila S, Parkkila AK, Opavsky R, Zelnik V, Saarnio J, Pastorek J (1997) Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology 112(2):398–408CrossRefPubMedGoogle Scholar
  43. Pelech S (2004) Tracking cell signaling protein expression and phosphorylation by innovative proteomic solutions. Curr Pharm Biotechnol 5:69–77CrossRefPubMedGoogle Scholar
  44. Pandey VK, Tusi S, Tusi Z, Raghubir R, Dixit M, Joshi MN, Bajpai SK (2004) Thiadiazolyl quinazolones as potential antiviral and antihypertensive agents. Indian J Chem 43B:180–183Google Scholar
  45. Parkkila S, Kivele AJ, Kaunisto K, Parkkila AK, Hakkola J, Rajaniemi H, Waheed A, Sly WS (2002) The plasma membrane carbonic anhydrase in murine hepatocytes identified as isozyme XIV. BMC Gastroenterol 2:13. doi: 10.1186/1471-230X-2-13 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Parkkila S, Parkkila AK, Rajaniemi H, Shah GN, Grubb JH, Waheed A, Sly WS (2001) Expression of membrane-associated carbonic anhydrase XIV on neurons and axons in mouse and human brain. Proc Natl Acad Sci USA 98(4):1918–1923CrossRefPubMedPubMedCentralGoogle Scholar
  47. Parkkila S, Rajaniemi H, Parkkila AK, Kivelä J, Waheed A, Pastorekova S, Pastorek J, Sly WS (2000) Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci USA 97:2220–2224CrossRefPubMedPubMedCentralGoogle Scholar
  48. Pastorek J, Pastorekova S, Callebaut I, Marnon JP, Zelnik V, Opavsky R, Zatovicova M, Liao S, Portetelle D, Stanbridge EJ, Zavada J, Burny A, Kettmann R (1994) Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene 9(10):2877–2888PubMedGoogle Scholar
  49. Patil R, Biradar JS (2001) Synthesis and pharmacological evaluation of Substituted–2-triazolo(3,4-b)[1,3,4,]-thiadiazoles. Indian J Pharm Sci 63(4):299–305Google Scholar
  50. Pattan SR, Kekare P, Dighe NS, Nirmal SA, Musmade DS, Parjane SK, Daithankar AV (2009) Synthesis and biological evaluation of some 1,3,4-thiadiazoles. J Chem Pharm Res 1(1):191–198Google Scholar
  51. Salimon J, Salih N, Yousif E, Hameed A, Ibraheem H (2010) Synthesis and antibacterial activity of some new 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives. Aust J Basic Appl Sci 4(7):2016–2021Google Scholar
  52. Sharma R, Sainy J, Chatuvedi SC (2008) 2-Amino-5-sulfanyl-1,3,4-thiadiazoles: a new series of selective cyclooxygenase-2 inhibitors. Acta Pharm 58(3):317–326PubMedGoogle Scholar
  53. Sharma R, Talesara GL, Nagda DP (2006) Synthesis of various isoniazidothiazolidinones and their imidoxy derivatives of potential biological interest. Arkivoc 1:1–12Google Scholar
  54. Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M (2007) Epik: a software program for pK (a) prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des 2007(12):681–691CrossRefGoogle Scholar
  55. Shen K, Cole PA (2003) Conversion of a tyrosin kinase protein substrate to a high affinity ligand by ATP linkage. J Am Chem Soc 125:16172–16173CrossRefPubMedGoogle Scholar
  56. Shrivastava SK, Shrivastava S, Shrivastava SD (1999) Synthesis of new carbazolyl-thiadiazole-2-oxoazetidines: antimicrobial, anticonvulsant and anti-inflammatory agents. Indian J Chem 38B:183–187Google Scholar
  57. Speck-Planche A, Kleandrova VV, Luan F, Cordeiro MNDS (2013) Unified multi-target approach for the rational in silico design of anti-bladder cancer agents. Anticancer Agents Med Chem 13(5):791–800CrossRefPubMedGoogle Scholar
  58. Speck-Planche A, Cordeiro MNDS (2014) Chemoinformatics for medicinal chemistry: in silico model to enable the discovery of potent and safer anti-cocci agents. Future Med Chem 6(18):2013–2028CrossRefPubMedGoogle Scholar
  59. Speck Planche A, Cordeiro MNDS (2017) Speeding up the virtual design and screening of therapeutic peptides: simultaneous prediction of anticancer activity and cytotoxicity. In: Speck-Planche A (ed) Multi-scale approaches in drug discovery: from empirical knowledge to in silico experiments and back, 1st edn. Elsevier, Oxford, p 127–147CrossRefGoogle Scholar
  60. Stillings MR, Welbourn AP, Walter DS (1986) Substituted 1,3,4-thiadiazoles with anticonvulsant activity. 2. Aminoalkyl derivatives. J Med Chem 29:2280–2284CrossRefPubMedGoogle Scholar
  61. Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7(2):168–181CrossRefPubMedGoogle Scholar
  62. Supuran CT, Scozzafava A (2000) Carbonic anhydrase inhibitors and their therapeutic potential. Expert Opin Ther Pat 10:575–600CrossRefGoogle Scholar
  63. Supuran CT, Scozzafava A, Casini A (2003) Carbonic anhydrase inhibitors and their therapeutic potential. Med Res Rev 23(2):146–189CrossRefPubMedGoogle Scholar
  64. Supuran CT, Scozzafava A, Conway I (2004) Carbonic anhydrase, its inhibitors and activators. CRC, New York, NYGoogle Scholar
  65. Svastova E, Hulikova A, Rafajova M, Zatovicova M, Gibadulinova A, Casini A, Cecchi A, Scozzafava A, Supuran CT, Pastorek J, Pastorekova S (2004) Hypoxia activates the capacity of tumour associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 577(3):439–445CrossRefPubMedGoogle Scholar
  66. Tan YT, Tillett DJ, Mckay IA (2000) Molecular strategies for overcoming antibiotic resistance in bacteria. Mol Med Today 6(8):309–314CrossRefPubMedGoogle Scholar
  67. Tureci O, Sahin U, Vollmar E, Siemer S, Gottert E, Seitz G, Parkkila AK, Shah GN, Grubb JH, Pfreundschuh M, Sly WS (1998) Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is over expressed in some renal cell cancers. Proc Natl Acad Sci USA 95(13):7608–7613. doi: 10.1073/pnas.95.13.7608 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Varandas LS, Fraga CAM, Miranda ALP, Barreiro EJ (2005) Design, synthesis and pharmacological evaluation of new nonsteroidal anti-inflammatory 1,3,4-thiadiazole derivatives. Lett Drug Des Discov 2(1):62–67CrossRefGoogle Scholar
  69. Vincent TA (2000) Current and future antifungal therapy: new targets for antifungal therapy. Int J Antimicrob Agents 16:317–321CrossRefGoogle Scholar
  70. Vyas VK, Jain A, Mahajan SC (2009) Insight into the structural requirement of 2-alkyl-4-(biphenylmethoxy) quinolones as nonpeptide angiotensin II receptor antagonist. Sci Pharma 77:33–45CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Mahavir Chhajed
    • 1
    • 2
  • Anil K. Shrivastava
    • 3
  • Atika Chhajed
    • 4
  • Vijay Taile
    • 5
  • Sumeet Prachand
    • 1
    • 2
  • Sanjay Jain
    • 1
  1. 1.Department of Pharmaceutical ChemistryIndore Institute of PharmacyIndoreIndia
  2. 2.Department of Pharmaceutical ChemistrySuresh Gyan Vihar UniversityJaipurIndia
  3. 3.Department of Pharmaceutical ChemistryNNM College of PharmacyNawabganj, GondaIndia
  4. 4.Department of Pharmaceutical ChemistryDr. A.P.J. Abdul Kalam UniversityIndoreIndia
  5. 5.Department of ChemistryR.T.M. Nagpur UniversityNagpurIndia

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