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p-TSA-promoted syntheses of 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogs: molecular modeling and in vitro antitumor activity against hepatocellular carcinoma

Authors Keshari AK, Singh AK, Raj V, Rai A, Trivedi P, Ghosh B, Kumar U, Rawat A, Kumar D, Saha S

Received 10 March 2017

Accepted for publication 12 April 2017

Published 29 May 2017 Volume 2017:11 Pages 1623—1642


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Tuo Deng

Amit K Keshari,1 Ashok K Singh,1 Vinit Raj,1 Amit Rai,1 Prakruti Trivedi,2 Balaram Ghosh,2 Umesh Kumar,3 Atul Rawat,3 Dinesh Kumar,3 Sudipta Saha1

1Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 2Department of Pharmacy, Birla Institute of Technology & Science Pilani, Hyderabad Campus, Hyderabad, Telangana State, 3Centre of Biomedical Research (CBMR), Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, India

Abstract: In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a p-toluenesulfonic acid (p-TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogs bearing a bridgehead nitrogen atom. This domino protocol constructed one new ring by the concomitant formation of multiple bonds (C–C, C–N, and C=N) involving multiple steps without the use of any metal catalysts in one-pot, with all reactants efficiently exploited. All the newly synthesized compounds were authenticated by means of Fourier transform infrared spectroscopy, liquid chromatography–mass spectrometry, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy, together with elemental analysis, and their antitumor activity was evaluated in vitro on a Hep-G2 human cancer cell line by sulforhodamine B assay. Computational molecular modeling studies were carried out on cancer-related targets, including interleukin-2, interleukin-6, Caspase-3, and Caspase-8. Two compounds (4A and 6A) showed growth inhibitory activity comparable to the positive control Adriamycin, with growth inhibition of 50% <10 µg/mL. The results of the comprehensive structure–activity relationship study confirmed the assumption that two or more electronegative groups on the phenyl ring attached to the thiazolo[2,3-b]quinazoline system showed the optimum effect. The in silico simulations suggested crucial hydrogen bond and π–π stacking interactions, with a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and molecular dynamics, in order to explore the molecular targets of HCC which were in complete agreement with the in vitro findings. Considering their significant anticancer activity, 4A and 6A are potential drug candidates for the management of HCC.

Keywords: thiazolo[3,2-a]pyrimidine and thiazolo[2,3-b]quinazoline, hepatocellular carcinoma, domino reactions, interleukins, caspases, molecular docking, ADMET, dynamics, multi-component reactions, metal-free

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