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Design, synthesis, in silico and biological evaluation of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)hydrazine carboxamides

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Abstract

A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)hydrazinecarboxamide derivatives has been successfully designed and synthesized to evaluate their potential as carbonic anhydrase (CA) inhibitors. The inhibitory potential of synthesized compounds against human CAI and CAII was evaluated. Compounds 3a–n exhibited \(\hbox {IC}_{50}\) values between \(1.89{-}415.1\,\upmu \hbox {M}\) against CAI and \(0.62{-}66.9\,\upmu \hbox {M}\) against CAII. Compound 3g was the most active inhibitor, with an \(\hbox {IC}_{50}\) value of \(0.62\,\upmu \hbox {M}\) against CAII. Molecular docking studies of compound 3g with CAII showed this compound fits nicely in the active site of CAII and it interacts with the zinc ion (\(\hbox {Zn}^{2+}\)) along with three histidine residues in the active site. Molecular dynamics simulation studies of compound 3g complexed with CAII also showed essential interactions which were maintained up to 40 ns of simulation. In vivo sub-acute toxicity study using 3g (300 mg/kg) was found non-toxic in adult Wistar rats.

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Acknowledgements

CBM and AP are thankful to the University Grants Commission (UGC) for the award of Dr. D.S. Kothari post-doctoral fellowship. SK and DI are thankful to UGC for the fellowship. MT thanks University of Delhi for financial assistance. The University Science Instrumentation Center (USIC), University of Delhi, is acknowledged for the recording NMR spectra of synthesized compounds. We thank Department of Science and Technology, India, for FIST support (SR/FST/LSI-541/2012). MIH thanks to the Council of Scientific and Industrial Research, India for the financial support (Grant No. 37(1665)/15/EMR-II).

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    Authors and Affiliations

    1. Bio-Organic Chemistry Laboratory, Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, North Campus, New Delhi, Delhi, 110007, India

      Shikha Kumari, Chandra Bhushan Mishra, Rajesh Yadav & Manisha Tiwari

    2. Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India

      Danish Idrees, Amresh Prakash & Md. Imtaiyaz Hassan

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    1. Shikha Kumari
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    Correspondence to Md. Imtaiyaz Hassan or Manisha Tiwari.

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    Shikha Kumari, Chandra Bhushan Mishra, Danish Idrees and Amresh Prakash have contributed equally.

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    Kumari, S., Mishra, C.B., Idrees, D. et al. Design, synthesis, in silico and biological evaluation of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)hydrazine carboxamides. Mol Divers 21, 163–174 (2017). https://doi.org/10.1007/s11030-016-9714-7

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