Novel aryl piperazines for alleviation of 'andropause' associated prostatic disorders and depression

  • Eur J Med Chem. 2017 May 26:132:204-218. doi: 10.1016/j.ejmech.2017.03.036.
Sonal Gupta  1 ,  Deepti Pandey  2 ,  Dhanaraju Mandalapu  3 ,  Vikas Sharma  2 ,  Mahendra Shukla  4 ,  Seema Singh  5 ,  Nidhi Singh  6 ,  Santosh Kumar Yadav  2 ,  Dilip Kumar Tanpula  7 ,  Surabhi Singh  8 ,  Jagdamba P Maikhuri  2 ,  Shubha Shukla  5 ,  Jawahar Lal  4 ,  Mohammad I Siddiqi  6 ,  Gopal Gupta  9 ,  Vishnu L Sharma  10
Affiliations
  • 1. Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
  • 2. Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
  • 3. Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
  • 4. Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
  • 5. Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
  • 6. Molecular & Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
  • 7. Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229010, India.
  • 8. Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229010, India.
  • 9. Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
  • 10. Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India. Electronic address: [email protected].
PMID: 28363155 DOI: 10.1016/j.ejmech.2017.03.036
Abstract

A series of seventeen piperazine derivatives have been synthesized and biologically evaluated for the management of andropause-associated prostatic disorders and depression. Five compounds 16, 19, 20, 21 and 22 significantly inhibited proliferation of androgen-sensitive LNCaP prostatic cell line with EC50 values of 12.4 μM, 15.6 μM, 11.8 μM, 10.4 μM, 12.2 μM respectively and decreased CA2+ entry through adrenergic-receptor α1A blocking activity. Anti-androgenic behaviour of compound 19 and 22 was evident by decreased luciferase activity. The high EC50 value in AR-negative cells PC3 and DU145 suggested that the cytotoxicity of compounds was due to AR down regulation. Compound 19 reduced the prostate weight of rats by 53.8%. Further, forced-swimming and tail-suspension tests revealed antidepressant-like activity of compound 19, lacking effects on neuromuscular co-ordination. In silico ADMET predictions revealed that the compound 19 had good oral absorption, aqueous solubility, non-hepatotoxic and good affinity for plasma protein binding. Pharmacokinetic and tissue uptake of 19 at 10 mg/kg demonstrated an oral bioavailability of 35.4%. In silico docking studies predicted similar binding pattern of compound 19 on Androgen Receptor as hydroxyflutamide. Compound 19 appears to be a unique scaffold with promising activities against androgen associated prostatic disorders in males like prostate Cancer and BPH and associated depression.

Keywords
MTT assay; Pharmacokinetics; Piperazine derivatives; α(1A) blocking activity.