Abstract
As part of an effort to establish a structure–activity relationship of diamidines against African trypanosomes, a quantitative correlation between molecular structure and anti-trypanosomal activity of 2-phenylbenzofuran derivatives was attained using classical quantitative structure–activity relationship (QSAR) descriptors and 3D similarity indices. A good model was obtained on the basis of classical descriptors; however, the model derived using descriptors based on similarity indices neither complemented the classical descriptors nor were significantly predictive. The best QSAR model with chemical descriptors that showed good correlative and predictive ability with r = 0.91, r 2 = 0.82, and r 2cv = 0.80 was developed using stepwise multiple linear regression analysis (MLR) and a comparable partial least squares analysis (PLS) model with r 2cv = 0.79 was also obtained. The QSAR models revealed that a substituent steric descriptor (Verloop B 1 parameter) and geometrical (moment of inertia 3 length) and hydrophobic (log P) descriptors of the whole molecule have significant impact on anti-trypanosomal activity of the compounds. The best QSAR models were validated by the leave one out technique. To further confirm the predictive power of the models, an external set of molecules was used which was not part of the training set. The high agreement betwPLS as shown in Eqeen experimental and predicted inhibitory values, obtained in the validation procedure, indicates the good quality of the derived QSAR models. In addition to QSAR analysis Lipinski’s rule was also applied to the series under consideration and newly designed molecules in order to check the drugability of the compounds; no violation of this rule was found. Hence 2-phenylbenzofuran has tremendous potential to yield orally active anti-trypanosomal agents.
Graphical abstract
Similar content being viewed by others
References
Barrett MP (1999) Lancet 353:1113
WHO Expert Committee (1998) Control and surveillance of African Trypanosomiasis. In: WHO Technical Report Series. World Health Organization, Geneva, vol 881. http://www.who.int; http://www.who.int/tdr
Enanga RJS, Burchmore ML, Barrett MP (2002) Cell Mol Life Sci 59:845
Welburn SC, Maudlin I (1999) Parasitol Today 15:399
Barrett MP (2000) Curr Opin Infect Dis 13:647
Nichols AC, Yielding L, Agbe SAO (2000) J Parasitol 86:177
Keiser J, Burri C (2000) Acta Tropica 74:101
Keiser J, Ericsson O, Burri C (2000) Clin Pharmacol Ther 67:478
Pepin J, Milord F (1994) Adv Parasitol 33:1
Legros D, Fournier C, Etchegorry MG, Maiso F, Szumilin E (1999) Bull Soc Pathol Exot 92:171
Legros D, Evans S, Maiso F, Enyaru JCK, Mbulamberi D (1999) Trans R Soc Trop Med Hyg 93:439
Barrett MP, Fairlamb AH (1999) Parasitol Today 15:136
Renslo AR, McKerrow JH (2006) Nat Chem Biol 2:701
Tidwell RR, Boyken DW (2003) In: Demeunynck M, Baelly C (eds) Small molecule DNA and RNA binders: from synthesis to nucleic acid complexes, vol 2. Wiley, Weinheim, p 414
Faerlamb AH (2003) Trends Parasitol 19:488
Bouteille B, Oukem O, Bisser S, Dumas MB (2003) Fundam Clin Pharmacol 17:171
Singh H, Sivakumar RJ (2004) Infect Chemother 10:307
Jannin J, Cattand P (2004) Curr Opin Infect Dis 17:565
Donkor IO, Huang TL, Tao B, Rattendi D, Lane S, Vargas M, Goldberg B, Bacchi C (2003) J Med Chem 46:1041
Wilson WD, Nguyen B, Tanious FA, Mathis A, Hall JE, Stephens CE, Boykin DW (2005) Curr Med Chem 5:389
Soeiro MNC, De Souza EM, Stephens CE, Boykin DW (2005) Expert Opin Invest Drugs 14:957
Dykstra CC, McClernon DR, Elwell LP, Tidwell RR (1994) Antimicrob Agents Chemother 38:1890
Bailly C, Dassonneville L, Carrascol C, Lucasl D, Kumar A, Boykin DW, Wilson WD (1999) Anti Cancer Drug Des 14:47
Fitzgerald DJ, Anderson JN (1999) J Biol Chem 274:27128
Henderson D, Hurley LH (1995) Nat Med (NY) 1:525
Paliwal SK, Pal M, Siddiqui AA (2009) Med Chem Res 19:475
Kurup A, Grag R, Carini DJ, Hansch C (2001) Chem Rev 101:2727
Athri P, Wenzler T, Ruiz P, Brun R, Boykin DW, Tidwell RR, Wilson WD (2006) Bioorg Med Chem 14:3144
Tropsha A, Cho SJ, Zheng W (1999) “New tricks for an old dog”: development and application of novel QSAR methods for rational design of combinatorial chemical libraries and database mining. In: Parrill AL, Reddy MR (eds) Rational drug design: novel methodology and practical applications, ACS Symposium Series 719. American Chemical Society, Washington, DC, p 198
Yao SW, Lopes VHC, Fernández F, García-Mera X, Morales M, Rodríguez-Borges JE, Cordeiroa MNDS (2003) Bioorg Med Chem 11:4999
Cramer RD (1993) Perspect Drug Discov Des 1:269
Verloop A, Tipker HW (1976) Development and application of new steric substituent parameters in drug design. In: Ariens EJ (ed) Drug design, vol 7. Academic, New York, p 165
Verloop A, Tipker J (1976) Pestic Sci 7:379
Verloop A, Tipker JA (1977) Comparative study of new parameters in drug design. In: Keverling BJA (ed) Biological activity and chemical structure. Elsevier, Amsterdam, p 63
Neidle S (2001) Nat Prod Rep 18:291
Lipinski CA, Lombardo F, Dominy DW, Feeney PJ (2001) Adv Drug Deliv Rev 46:3
Bakunov SA, Bakunova SM, Wenzler T, Barszcz T, Werbovetz KA, Brun R, Tidwell RR (2008) J Med Chem 51:6927
Sadowski J, Gasteiger (1993) J Chem Rev 93:2567
Wu W, Walczak B, Massart DL, Heuerding S, Erni F, Last IR, Prebble KA (1996) Chemometr Intell Lab Syst 33:35
Yasri A, Hartsough DJ (2001) Chem Inf Comput Sci 41:1218
Burt C, Richards GWJ (1990) Comput Aided Mol Des 4:231
Carbo R, Leyda L, Arnau M (1980) Int J Quantum Chem 17:1185
Good AC, So SS, Richards WG (199) J Med Chem 36:433
Good AC, Peterson SJ, Richards WG (1993) J Med Chem 36:2929
Burt G, Huxley P, Richards WG (1990) J Comput Chem 11:1139
Kubinyi H, Hamprecht FA, Mietzner T (1998) J Med Chem 41:2553
Si HZ, Wang T, Zhang KJ, Hu ZD, Fan BT (2006) Bioorg Med Chem 14:4834
Adams MJ (1995) Chemometrics in analytical spectroscopy. Royal Society of Chemistry, Cambridge
Nosov VN (1990) Computational biometrics. Moscow University Press, Moscow (in Russian)
Rameshwar N, Krishna K, Ashok KB, Parthasarathy T (2006) Bioorg Med Chem 14:319
Kim D, Hong S, Lee D (2006) Int J Mol Sci 7:485
Golbraikh A, Tropsha A (2002) J Mol Graphics Model 20:269
Tropsha A, Gramatica P, Gombar VK (2003) QSAR Comb Sci 22:69
Acknowledgments
The authors pay sincere thanks to Prof. Aditya Shastri, Vice Chancellor, Banasthali University, Rajasthan, India for providing necessary computational facilities for the completion of the study in a convenient manner.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Paliwal, S.K., Verma, A.N. & Paliwal, S. Structure–activity relationship analysis of cationic 2-phenylbenzofurans as potent anti-trypanosomal agents: a multivariate statistical approach. Monatsh Chem 142, 1069–1086 (2011). https://doi.org/10.1007/s00706-011-0509-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00706-011-0509-3