3D QSAR ANALYSIS ON OXADIAZOLE DERIVATIVES AS ANTICANCER AGENTS
Abstract
Three dimensional quantitative structure activity relationship (3D QSAR) study by means of partial least square regression (PLSR) method was performed on a series of 3-(Aryl)-N-(Aryl)-1, 2, 4-Oxadiazol-5-amines as antiproliferative agents using molecular design suite (VLifeMDS). This study was performed with 20 compounds (data set) using sphere exclusion (SE) algorithm and manual selection method used for the division of the data set into training and test set. PLSR methodology with stepwise (SW) forward-backward variable selection method was used for building the QSAR models. Five predictive models were generated with sphere exclusion and two with manual data selection methods using PLSR. The most significant model is having correlation coefficient 0.9334 (squared correlation coefficient r2 = 0.8713) indicating noteworthy correlation between biological activity and descriptors. The model has internal predictivity 74.45% (q2 = 0.7445) and highest external predictivity 81.09 % (pred_r2 = 0.8109) and lowest error term for predictive correlation coefficient (pred_r2se = 0.1321). Model showed that steric (S_1278, S_751) and electrostatic (E_307) interactions play important role in determining antiproliferative activity. The molecular field analysis (MFA) contour plots provided further understanding of the relationship between structural features of substituted oxadiazole derivatives and their activities which should be applicable to design newer potential antiproliferative agents.
Keywords:
3D-QSAR, PLS, antiproliferative agents, 1, 2, 4-Oxadiazoles.DOI
https://doi.org/10.25004/IJPSDR.2011.030314References
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11. Song Y, Connor DT, Sercel AD, Sorenson RJ, Doubleday R, Unangst PC, Roth BD, Beylin VG, Gilbertsen RB, Chan K, Schrier DJ, Guglietta A, Bornemeier DA, Dyer RD. Synthesis, structure e activity relationships and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series. J Med Chem. 1999; 42:1151-1160.
12. Farooqui M, Bora R, Patil CR. Synthesis, analgesic and anti-inflammatory activities of novel 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles. Eur J Med Chem. 2009; 44:794-799.
13. Nicolaides DN, Fylaktakidou KC, Litinas KE, Hadjipavlou-Litina D. Synthesis and biological evaluation of several coumarin-4-carboxamidoxime and 3-(coumarin-4-yl)-1, 2, 4-oxadiazole derivatives. Eur J Med Chem. 1998; 33: 715-724.
14. Bezerra NMM, de Oliveira SP, Srivastava RM, da Silva JR. Synthesis of 3-aryl-5-decapentyl-1,2,4-oxadiazoles possessing anti-inflammatory and antitumor properties. Farmaco 2005; 60: 955-960.
15. Leite ACL, Vieira RF, de Faria AR, Wanderley AG, Afiatpour P, Ximenes ECPA, Srivastava RM, Oliveira CF, Medeiros MV, Antunes E, Brondani DJ. Synthesis, anti-inflammatory and antimicrobial activities of new 1, 2, 4-oxadiazoles peptidomimetics. Farmaco 2000; 55: 719-724.
16. Wu WD, Ma LT, Zhang LH, Lu Y, Guo F, Zheng QT. Cerium(III) chloride promoted addition of organometallic reagents to (−)-menthone—preparation of chiral neomenthyl derivatives. Tetrahedron Asymm. 2000; 11: 1527-1536.
17. Watthey JWH, Desai M, Rutledge R, Dotson R. Synthesis and diuretic profile of 3-(3-amino-1,2,4-oxadiazol-5-yl)-5-chloro-2,6-pyrazinediamine, an amiloride-type diuretic. J Med Chem. 1980; 23: 690-692.
18. Haugwitz RD, Martinez AJ, Venslavsky J, Angel RG, Maurer BV, Jacobs GA, Narayanan VL, Cruthers LR, Szanto J. Antiparasitic agents. 6. Synthesis and anthelmintic activities of novel isothiocyanatophenyl-1, 2, 4-oxadiazoles. J Med Chem. 1985; 28: 1234-1241.
19. Ainsworth C, Buting WE, Davenport J, Callender ME, McCowen MC. Anthelmintic Activity of 1, 2, 4-Oxadiazoles. J Med Chem. 1967; 10: 208-211.
20. Weidner-Wells MA, Henninger TC, Fraga-Spano SA, Boggs CM, Matheis M, Ritchie DM, Argentieri DC, Wachter MP, Hlasta DJ. Synthesis and structure–activity relationships of 3, 5-diarylisoxazoles and 3, 5-diaryl-1, 2, 4-oxadiazoles, novel classes of small molecule interleukin-8 (IL-8) receptor antagonists. Bioorg Med Chem Lett. 2004; 14: 4307–4311.
21. Chimirri A, Grasso S, Montforte AM, Rao A, Zappala M. Synthesis and Antitumor Activity Evaluation of δ2-1,2,4- Oxadiazoline Derivatives. Farmaco 1996; 51: 125-129.
22. Lankau HJ, Unverferth K, Grunwald C, Hartenhauer H, Heinecke K, Katrin Berno¨ster, Rita Dost, Ute Egerland, Chris Rundfeldt. New GABA-modulating 1, 2, 4-oxadiazole derivatives and their anticonvulsant activity. Eur J Med Chem. 2007; 42: 873-879.
23. Luthman K, Borg S, Hacksell U. Synthesis and Use of Pseudopeptides Derived from 1, 2, 4-Oxadiazole- 1, 3, 4-Oxadiazole-, and 1, 2, 4-Triazole-based Dipeptidomimetics. Methods Mol Med. 1999; 1-23.
24. Zhang HZ, Kasibhatla S, Kuemmerle J, Kemnitzer W, Ollis-Mason K, Qiu L, Crogan-Grundy C, Tseng B, Drewe J, Cai SX. Discovery and Structure-Activity Relationship of 3-Aryl-5-aryl-1, 2, 4-oxadiazoles as a New Series of Apoptosis Inducers and Potential Anticancer Agents. J Med Chem. 2005; 48: 5215-5223.
25. Matsumoto J, Takahashi T, Agata M, Toyofuku H, Sasada N. A study of the biological pharmacology of IFO, a new selective and reversible monoamine oxidase-B inhibitor. Jpn J Pharmacol. 1994; 65: 51-57.
26. Boys ML, Schretzman LA, Chandrakumar NS, Tollefson MB, Mohler SB, Downs VL, Wang Y, Dalton CR, Norring SA. Convergent, parallel synthesis of a series of β-substituted 1, 2, 4-oxadiazole butanoic acids as potent and selective αvβ3 receptor antagonists. Bioorg Med Chem Lett. 2006; 16: 839–844.
27. Jessen KA, English NM, Wang JY, Maliartchouk S, Archer SP, Qiu L, Brand R, Kuemmerle J, Zhang HZ, Gehlsen K, Drewe J, Tseng B, Cai SX, Kasibhatla S. The discovery and mechanism of action of novel tumor-selective and apoptosis-inducing 3, 5-diaryl-1, 2, 4-oxadiazole series using a chemical genetics approach. Mol Cancer Ther 2005; 4(5): 761-771.
28. Krasavin M, Rufanov KA, Sosnov AV, Karapetian R, Godovykh E, Soldatkina O, Lavrovsky Y, Gakh AA. Discovery and SAR exploration of N-aryl-N-(3-aryl-1, 2, 4-oxadiazol-5-yl) amines as potential therapeutic agents for prostate cancer. Chem Centr J. 2010; 4: 4-10.
29. Than GN, Turoczy T, Sumegi B, Than NG, Bellyei S, Bohn H, Szekeres G. Over expression of placental tissue protein 17b/TIP47 in cervical dysplasias and cervical carcinoma. Anticancer Res. 2001; 21: 639-642.
30. Kemnitzer W, Kuemmerle J, H-Zhang Z, Kasibhatla S, Tseng B, Drewe J, Cai SX. Discovery of 3-aryl-5-aryl-1, 2, 4-oxadiazoles as a new series of apoptosis inducers. 2. Identification of more aqueous soluble analogs as potential anticancer agents. Bioorg. Med. Chem. Lett. 2009; 19: 4410-4415.
31. Ferreira MMC. Multivariate QSAR. J Braz Chem Soc. 2002; 13: 742.
32. VLifeMDS 3.5, Molecular Design Suite, Vlife Sciences Technologies Pvt. Ltd., Pune, India (2009), www.vlifesciences.com.
33. Zheng W, Topsha A. Novel variable selection quantitative structure--property relationship approach based on the k-nearest-neighbor principle. J Chem Inf Comput Sci. 2000; 40: 185-194.
34. Ajmani S, Kamaiakar J, Kulkarni SA. Three-Dimensional QSAR Using the k-Nearest Neighbor Method and Its Interpretation. J Chem Inf Model 2006; 46: 24-31.
35. Rogers D, Hopfinger AJ. Application of Genetic Function Approximation to Quantitative Structure-Activity Relationships and Quantitative Structure-Property Relationships. J Chem Inf Comp Sci. 1994; 34: 854-866.
2. Orlek BS, Blaney FE, Brown F, Clark MS, Hadley MS, Hatcher J, Riley GJ, Rosenberg, HE, Wadsworth HJ, Wyman P. Comparison of azabicyclic esters and oxadiazoles as ligands for the muscarinic receptor. J Med Chem. 1991; 34: 2726-2735.
3. Clitherow JW, Beswick P, Irving WJ, Scopes DIC, Barnes JC, Clapham J, Brown JD, Evans DJ, Hayes, AG. Novel 1, 2, 4-oxadiazoles as potent and selective histamine H3 receptor antagonists. Bioorg Med Chem Lett. 1996; 6: 833-838.
4. Krämer I, Schunack W. H2-Antihistaminics. 25. Synthesis and H2-antagonistic activity of monosubstituted 1, 2, 4-oxadiazole-3, 5-diamines. Arch Pharm (Weinheim) 1985; 318: 888-895.
5. Krämer I, Schunack W. Synthesis and H-2 antagonistic activity of N-3, N-5-substituted 1, 2, 4-oxadiazole-3, 5-diamines. 26. H-2 antihistaminics. Arzheim Forsch. /Drug Res. 1986; 36: 1011-1014.
6. Yurugi S, Miyake A, Fushimi T, Imamiya E, Matsamura H, Imai Y. Studies on the synthesis of N-heterocyclic compounds. 3. Hypocholesterolemic 1, 2, 4- oxadiazole derivatives. Chem Pharm Bull. 1973; 21: 1641-1650.
7. Diana GD, Volkots DL, Nitz TJ, Bailey TR, Long MA, Vescio N, Aldous S, Pevear DC, Dutko FJ. Oxadiazoles as ester bioisosteric replacements in compounds related to disoxaril-antirhinovirus activity. J Med Chem. 1994; 37: 2421-2436.
8. Showell GA, Gibbons TL, Kneen CO, MacLeod AM, Merchant K, Saunders J, Freedman SB, Patel S, Baker R. Tetrahydropyridyloxadiazoles: semi-rigid muscarinic ligands. J Med Chem. 1991; 34: 1086-1094.
9. Street LJ, Baker R, Book T, Kneen CO, MacLeod AM, Merchant KJ, Showell GA, Saunders J, Herbert RH, Freedman SB, Harley EA. Synthesis and biological activity of 1,2,4-oxadiazole derivatives as highly potent and efficacious agonists for cortical muscarinic receptors. J Med Chem. 1990; 33: 2690-2697.
10. Unangst PC, Shrum GP, Connor DT, Dyer RD, Schrier DJ. Novel 1, 2, 4-oxadiazoles and 1, 2, 4-thiadiazoles as dual 5-lipoxygenase and cyclooxygenase inhibitors. J Med Chem. 1992; 35: 3691-3698.
11. Song Y, Connor DT, Sercel AD, Sorenson RJ, Doubleday R, Unangst PC, Roth BD, Beylin VG, Gilbertsen RB, Chan K, Schrier DJ, Guglietta A, Bornemeier DA, Dyer RD. Synthesis, structure e activity relationships and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series. J Med Chem. 1999; 42:1151-1160.
12. Farooqui M, Bora R, Patil CR. Synthesis, analgesic and anti-inflammatory activities of novel 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles. Eur J Med Chem. 2009; 44:794-799.
13. Nicolaides DN, Fylaktakidou KC, Litinas KE, Hadjipavlou-Litina D. Synthesis and biological evaluation of several coumarin-4-carboxamidoxime and 3-(coumarin-4-yl)-1, 2, 4-oxadiazole derivatives. Eur J Med Chem. 1998; 33: 715-724.
14. Bezerra NMM, de Oliveira SP, Srivastava RM, da Silva JR. Synthesis of 3-aryl-5-decapentyl-1,2,4-oxadiazoles possessing anti-inflammatory and antitumor properties. Farmaco 2005; 60: 955-960.
15. Leite ACL, Vieira RF, de Faria AR, Wanderley AG, Afiatpour P, Ximenes ECPA, Srivastava RM, Oliveira CF, Medeiros MV, Antunes E, Brondani DJ. Synthesis, anti-inflammatory and antimicrobial activities of new 1, 2, 4-oxadiazoles peptidomimetics. Farmaco 2000; 55: 719-724.
16. Wu WD, Ma LT, Zhang LH, Lu Y, Guo F, Zheng QT. Cerium(III) chloride promoted addition of organometallic reagents to (−)-menthone—preparation of chiral neomenthyl derivatives. Tetrahedron Asymm. 2000; 11: 1527-1536.
17. Watthey JWH, Desai M, Rutledge R, Dotson R. Synthesis and diuretic profile of 3-(3-amino-1,2,4-oxadiazol-5-yl)-5-chloro-2,6-pyrazinediamine, an amiloride-type diuretic. J Med Chem. 1980; 23: 690-692.
18. Haugwitz RD, Martinez AJ, Venslavsky J, Angel RG, Maurer BV, Jacobs GA, Narayanan VL, Cruthers LR, Szanto J. Antiparasitic agents. 6. Synthesis and anthelmintic activities of novel isothiocyanatophenyl-1, 2, 4-oxadiazoles. J Med Chem. 1985; 28: 1234-1241.
19. Ainsworth C, Buting WE, Davenport J, Callender ME, McCowen MC. Anthelmintic Activity of 1, 2, 4-Oxadiazoles. J Med Chem. 1967; 10: 208-211.
20. Weidner-Wells MA, Henninger TC, Fraga-Spano SA, Boggs CM, Matheis M, Ritchie DM, Argentieri DC, Wachter MP, Hlasta DJ. Synthesis and structure–activity relationships of 3, 5-diarylisoxazoles and 3, 5-diaryl-1, 2, 4-oxadiazoles, novel classes of small molecule interleukin-8 (IL-8) receptor antagonists. Bioorg Med Chem Lett. 2004; 14: 4307–4311.
21. Chimirri A, Grasso S, Montforte AM, Rao A, Zappala M. Synthesis and Antitumor Activity Evaluation of δ2-1,2,4- Oxadiazoline Derivatives. Farmaco 1996; 51: 125-129.
22. Lankau HJ, Unverferth K, Grunwald C, Hartenhauer H, Heinecke K, Katrin Berno¨ster, Rita Dost, Ute Egerland, Chris Rundfeldt. New GABA-modulating 1, 2, 4-oxadiazole derivatives and their anticonvulsant activity. Eur J Med Chem. 2007; 42: 873-879.
23. Luthman K, Borg S, Hacksell U. Synthesis and Use of Pseudopeptides Derived from 1, 2, 4-Oxadiazole- 1, 3, 4-Oxadiazole-, and 1, 2, 4-Triazole-based Dipeptidomimetics. Methods Mol Med. 1999; 1-23.
24. Zhang HZ, Kasibhatla S, Kuemmerle J, Kemnitzer W, Ollis-Mason K, Qiu L, Crogan-Grundy C, Tseng B, Drewe J, Cai SX. Discovery and Structure-Activity Relationship of 3-Aryl-5-aryl-1, 2, 4-oxadiazoles as a New Series of Apoptosis Inducers and Potential Anticancer Agents. J Med Chem. 2005; 48: 5215-5223.
25. Matsumoto J, Takahashi T, Agata M, Toyofuku H, Sasada N. A study of the biological pharmacology of IFO, a new selective and reversible monoamine oxidase-B inhibitor. Jpn J Pharmacol. 1994; 65: 51-57.
26. Boys ML, Schretzman LA, Chandrakumar NS, Tollefson MB, Mohler SB, Downs VL, Wang Y, Dalton CR, Norring SA. Convergent, parallel synthesis of a series of β-substituted 1, 2, 4-oxadiazole butanoic acids as potent and selective αvβ3 receptor antagonists. Bioorg Med Chem Lett. 2006; 16: 839–844.
27. Jessen KA, English NM, Wang JY, Maliartchouk S, Archer SP, Qiu L, Brand R, Kuemmerle J, Zhang HZ, Gehlsen K, Drewe J, Tseng B, Cai SX, Kasibhatla S. The discovery and mechanism of action of novel tumor-selective and apoptosis-inducing 3, 5-diaryl-1, 2, 4-oxadiazole series using a chemical genetics approach. Mol Cancer Ther 2005; 4(5): 761-771.
28. Krasavin M, Rufanov KA, Sosnov AV, Karapetian R, Godovykh E, Soldatkina O, Lavrovsky Y, Gakh AA. Discovery and SAR exploration of N-aryl-N-(3-aryl-1, 2, 4-oxadiazol-5-yl) amines as potential therapeutic agents for prostate cancer. Chem Centr J. 2010; 4: 4-10.
29. Than GN, Turoczy T, Sumegi B, Than NG, Bellyei S, Bohn H, Szekeres G. Over expression of placental tissue protein 17b/TIP47 in cervical dysplasias and cervical carcinoma. Anticancer Res. 2001; 21: 639-642.
30. Kemnitzer W, Kuemmerle J, H-Zhang Z, Kasibhatla S, Tseng B, Drewe J, Cai SX. Discovery of 3-aryl-5-aryl-1, 2, 4-oxadiazoles as a new series of apoptosis inducers. 2. Identification of more aqueous soluble analogs as potential anticancer agents. Bioorg. Med. Chem. Lett. 2009; 19: 4410-4415.
31. Ferreira MMC. Multivariate QSAR. J Braz Chem Soc. 2002; 13: 742.
32. VLifeMDS 3.5, Molecular Design Suite, Vlife Sciences Technologies Pvt. Ltd., Pune, India (2009), www.vlifesciences.com.
33. Zheng W, Topsha A. Novel variable selection quantitative structure--property relationship approach based on the k-nearest-neighbor principle. J Chem Inf Comput Sci. 2000; 40: 185-194.
34. Ajmani S, Kamaiakar J, Kulkarni SA. Three-Dimensional QSAR Using the k-Nearest Neighbor Method and Its Interpretation. J Chem Inf Model 2006; 46: 24-31.
35. Rogers D, Hopfinger AJ. Application of Genetic Function Approximation to Quantitative Structure-Activity Relationships and Quantitative Structure-Property Relationships. J Chem Inf Comp Sci. 1994; 34: 854-866.
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01-07-2011
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“3D QSAR ANALYSIS ON OXADIAZOLE DERIVATIVES AS ANTICANCER AGENTS”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 3, no. 3, July 2011, pp. 230-5, https://doi.org/10.25004/IJPSDR.2011.030314.
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“3D QSAR ANALYSIS ON OXADIAZOLE DERIVATIVES AS ANTICANCER AGENTS”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 3, no. 3, July 2011, pp. 230-5, https://doi.org/10.25004/IJPSDR.2011.030314.
