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Design, Synthesis, and Molecular Modeling of Asymmetric Tolterodine Derivatives as Anticancer Agents
Author(s) -
Dakarapu Veera venkatarao,
Allaka Tejeswara Rao,
Uppalla Lav Kumar,
Jha Anjali
Publication year - 2018
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.3274
Subject(s) - chemistry , hydrogen bond , stereochemistry , autodock , dissociation constant , docking (animal) , ligand (biochemistry) , proton nmr , combinatorial chemistry , molecule , organic chemistry , receptor , biochemistry , in silico , medicine , nursing , gene
An efficient and short enantioselective synthesis of (S)‐ and (R)‐tolterodine acid isomers ( 7a – 7i ) was performed a 6‐methyl‐4‐phenylchroman‐2‐one intermediate from inexpensive and commercially available starting materials. A series of tolterodine acid hybrids 7 were synthesized and characterized by infrared, 1 H NMR, 13 C NMR, X‐ray diffraction, and mass spectral analysis followed by anticancer activity on human cancer cell lines including A549 and SKNSH. Our results revealed the final compounds exhibited moderate to potent activity against A549 and SKNSH. Compounds 7g and 7f were more cytotoxic than cisplatin against all tested two human cancer cell lines, with half maximal inhibitory concentration values of 13.2, 14.3, and 8.5 μ M , respectively. In the present investigation, possible binding interaction of the target compounds with 3IVX protein, ligand conformations, including hydrogen bonds and the bond lengths, was analyzed. AutoDock 4.2 chemokine receptor has been investigated by molecular docking and was used to predict the affinity, activity, and binding orientation of ligand with the target protein and to analyze best conformations. Compound 7h exhibited more binding energy (ΔG = −5.52 kcal/mol) and dissociation constant (KI = 89.8 μ M ) with amino acids Glu 17 and Thr 87 interacting. Further studies are warranted to fully evaluate the analogues as the potential prodrugs with improved physiochemical properties.