1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone for androgen sensitive prostatic disorders

1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone

CAS 330633-91-5

CDRI-?

For treatment of androgen sensitive prostatic disorders

1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone

In the quest for novel scaffolds for the management of androgen sensitive prostatic disorders like prostate cancer and benign prostatic hyperplasia, a series of twenty-six aryl/heteroaryl piperazine derivatives have been described. Three compounds, 8a, 8c and 9a, exhibited good activity profiles against an androgen sensitive prostate cancer cell line (LNCaP) with EC₅₀values of 9.8, 7.6 and 11.2 μM, respectively. These compounds caused a decrease in luciferase activity and a decline in PSA and Ca²⁺ levels, which are indicative of their anti-androgenic and α_1A-adrenergic receptor blocking activities, respectively.

Compound 9a reduced the prostate weight of rats (47%) and in pharmacokinetic analysis at 10 mg kg⁻¹ it demonstrated an MRT of ∼14 h post dose, exhibiting high levels in prostate. Compound 9a docked in a similar orientation to hydroxyflutamide on an androgen receptor and showed strong π–π interactions. These findings reveal that compound 9a is a promising candidate for management of prostatic disorders with anti-androgenic and α_1A-blocking activities.

1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone (9a) To the mixture of 8a (0.3 g, 1.06 mmol) and Et3N (0.3 mL, 2.12 mmol) in CHCl3 (5 mL) was added 1-(4-nitrophenyl)piperazine (7a, 0.320 g, 1.59 mmol) in 5 mL CHCl3 dropwise within 1 h. After complete addition reaction mixture was further stirred in an oil bath at 80-85 °C for 15 h. The reaction mixture was cooled, washed with water (5 mL × 3) and the organic layer was separated. Combined organic layer was dried (anhyd. Na2SO4 and concentrated under reduced pressure in rotavapor. The solid obtained was purified by recrystallization using EtOAc/Hexane which furnished yellow crystals (yield 81%);

mp: 156-157 °C; IR (KBr)  (cm-1): 3019, 2399, 1640, 1597, 1506, 1423, 1330;

1H NMR (400 MHz, CDCl3):  8.14-8.09 (4H, m), 6.84-6.81 (4H, m), 3.84-3.83 (4H, m), 3.49-3.44 (8H, m), 3.33 (2H, s), 2.72 (4H, t, J = 5.0 Hz);

13C NMR (75.4 MHz, CDCl3):  167.7, 154.7, 154.3, 138.8, 138.4, 125.9, 125.8, 112.9, 112.7, 60.8, 52.5, 46.9, 46.7, 44.6;

HRMS (ESI positive) m/z calcd. for C22H26N6O5 [M+H]+ : 455.2043, found: 455.2034;

Anal calcd. for C22H26N6O5: C, 58.14; H, 5.77; N, 18.49, found: C, 58.31; H, 5.92; N, 18.66.

SONAL GUPTA

Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram ext., Lucknow-226031, India

Dr. VISHNU LAL SHARMA

http://www.cdriindia.org/VL_Sharma.htm

Dr. VISHNU LAL SHARMA
	Senior Principal Scientist (CSIR-CDRI ) / Professor (AcSIR) Lab No. CSS-SF-201, Medicinal and Process Chemistry Division Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road Lucknow- 226031
Educational Qualifications M.Sc (Organic Chemistry, Lucknow University, Lucknow, Uttar Pradesh, 1978) Ph.D. (Chemistry, Lucknow University, Lucknow, Uttar Pradesh, 1985) Date of Birth February 7th, 1958 E- Mail vl_sharma@cdri.res.in, vlscdri@gmail.com Phone No. +91-0522-2772450/550, Ext. 4671. Mobile No. +91-9415074195 Fax No. +91-522-2771941 Research Experience (Area) Medicinal chemistry, Organic chemistry. Google Scholar https://scholar.google.co.in/citations?user=cAsQaiYAAAAJ&hl=en Research gate https://www.researchgate.net/profile/Vishnu_Sharma13
POST-DOCTORAL RESEARCH (ABROAD)
• University of Dusseldorf, Dusseldorf, Germany, Oct., 1994 to Dec., 1994
CURRENT AREAS OF INTEREST
• Medicinal Chemistry, Synthetic organic chemistry and Process chemistry. • The research focused in my group is related to design and synthesis of small molecule libraries of biomedical importance and development of new methodologies and process developments of candidate drugs.
From left to right upper row: Dr. S.T.V.S. Kiran Kumar, Dr. Lalit Kumar, Dr. V.L. Sharma, Dr. Nand Lal, Dr. Amit Sarswat Lower row: Dhanaraju Mandalapu, Sonal Gupta, Mrs. Tara Rawat (S.T.O.), Dr. Veenu bala, Dr. Santosh Jangir
THESIS SUPERVISED
• Seven (7) students for their Ph.D. • Twenty two (22) students for their Post Graduation degrees
FORMER Ph.D. STUDENTS
• Dr. S.T.V.S. Kiran Kumar, 2006,Research Scientist at University of Virginia Charlottesville, Virginia. • Dr. Lalit Kumar, 2011, KIMIA Biosciences Pvt.Ltd., Rajasthan, India . • Dr. Amit Sarswat, 2011, Postdoctoral Fellow, University Health Network, Toronto, Ontario, Canada. • Dr. Nand Lal, 2012, Scientist E1 at HLL-Lifecare Limited, Thiruvananthapuram, Kerala, India. • Dr. Santosh Jangir, 2014. • Dr. Veenu bala, 2014, Assistant Professor at Mohan Lal Sukhdia University, Rajasthan, India. • Ms. Sonal Gupta, 2015.
FORMER PROJECT ASSISTANTS
• Ms. Mala Singh (2014-2016)
PRESENT Ph.D. STUDENTS
• Mr. Dhanaraju Mandalapu (CSIR-SRF; 2012-present)
FORMER POSTGRADUATE STUDENTS
• M. Jay Kothari (1997) • A.N. Misra (1997) • Ritu Chadda (1998) • Arun Kumar Misra (2000) • S.Nitya (2003) • Vishwanath Pratap Gupta (2004) • Divya (2006) • Charu Mahawar (2007) • Desh Deepak Pandey (2008) • Priyanka Pandey (2010) • Sumit Kumar (2010) • Sourabh Maheswari (2011) • Kartheek Nandikonda (2012) • Naveen Gupta (2012) • Pallavi Nayak (2012) • Neetika (2013) • Vikas Kumar (2013) • Neha Yadav (2013) • Subhadra Thakur (2014) • Jitendra Kumar (2015) • Suyash Tewari (2015) • Anjali Misra (2015)
MEMBERSHIP OF SOCIETES :
1. The Uttar Pradesh Association for Advancement of Science, Lucknow (India) 2. Indian Chemical Society (Calcutta) 3. Chemical Research Society of India, (Bangalore)
PROJECTS:
Reproductive Health Research: Male Reproductive Health and Contraception 1 Co – Principal Investigator: “Designed synthesis, evaluation and identification of novel, dually-effective spermicidal agents with anti-Trichomonal activity for ‘prophylactic’ contraception” (July 2014 – ongoing ), Funded by DHR, Indian council of Medical Research (ICMR), New Delhi. 2 Co-Principal Investigator: “Preclinical development of S,S’-Disulfanediylbis(pyrrolidinopropane-2,1-diyl) bis (piperidinothiocarbamate) as a vaginal contraceptive” (July 2011 – June 2013), Funded by Indian council of Medical Research (ICMR), New Delhi. 3 Principal Investigator: “Designed synthesis and biological evaluation of novel agents for management of benign prostatic hyperplasia” (November 2012 – October 2015), Funded by Indian council of Medical Research (ICMR), New Delhi.
PUBLICATIONS & PATENTS-
Total number of peer reviewed publications- 69 (Sixty Nine ) Total number of patents: (1 World patent and 4 National patents) – 5 (Five) Citations to all publications: -Sum of times cited – 486, h-index- 12
SELECTED PUBLICATIONS
• Dhanaraju Mandalapu, Deependra Kumar Singh, Sonal Gupta, Vishal M. Balaramnavar, Mohammad Shafiq, Dibyendu Banerjee, Vishnu Lal Sharma. Discovery of monocarbonyl curcumin hybrids as a novel class of human DNA ligase I inhibitors: in silico design, synthesis and biology. RSC Advances, 2016, 6, 26003. • Subhashis Pal, Kainat Khan, Shyamsundar Pal China, MonikaMittal, Konica porwal, Richa Shrivastava, Isha Taneja, Zakir Hossain, Dhanaraju Mandalapu, Jiaur R. Gayen, Muhammad Wahajuddin, Vishnu Lal Sharma, Arun K. Trivedi, Sabyasachi Sanyal, Smrati Bhadauria, Madan M. Godbole , Sushil K. Gupta, Naibedya Chattopadhyay. Theophylline, a methylxanthine drug induces osteopenia and alters calciotropic hormones and prophylactic vitamin D treatment protects against these changes in rats. Toxicology and Applied Pharmacology, 2016, 295, 12-25. • Bhavana Kushwaha, Dhanaraju Mandalapu, Veenu Bala, Lokesh Kumar, Aastha Pandey, Deepti Pandey, Santosh Kumar Yadav, Pratiksha Singh, P.K. Shukla, Jagdamba P. Maikhuri, Satya N. Sankhwar, Vishnu L. Sharma, Gopal Gupta. Ammonium salts of carbamodithioic acid as potent vaginal trichomonacides and fungicides. International Journal of Antimicrobial Agents, 2016, 47, 36-47. • Dhanaraju Mandalapu, Nand Lal, Lokesh Kumar, Bhavana Kushwaha, Sonal Gupta, Lalit Kumar, Veenu Bala, Santosh K. Yadav, Pratiksha Singh, Nidhi Singh, Jagdamba P. Maikhuri, Satya N. Sankhwar, Praveen K. Shukla, Imran Siddiqi, Gopal Gupta, Vishnu L. Sharma. Innovative Disulphide Esters of Dithiocarbamic acid as Women Controlled Contraceptive Microbicides: A Bioisosterism Approach. ChemMedChem, 2015, 10, 1739-1753. • Rachumallu Ramakrishna, Santosh kumar Puttrevu, Manisha Bhateria,Veenu Bala,Vishnu L. Sharma, Rabi Sankar Bhatta. Simultaneous determination of azilsartan and chlorthalidone in rat and human plasma by liquid chromatography-electrospray tandemmass spectrometry. Journal of Chromatography B, 2015,990, 185–197. • Hardik Chandasana, Yashpal S. Chhonkera, Veenu Bala, Yarra D. Prasad ,Telaprolu K. Chaitanya, Vishnu L. Sharma, Rabi S. Bhatta. Pharmacokinetic bioavailability, metabolism and plasma proteinbinding evaluation of NADPH-oxidase inhibitor apocynin using LC–MS/MS. Journal of Chromatography B, 2015, 985, 180–188. • Rajeev Kumar, Vikas Verma, Vikas Sharma, Ashish Jain, Vishal Singh, Amit Sarswat , Jagdamba P. Maikhuri, Vishnu L. Sharma, Gopal Gupta. A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors. Toxicology and Applied Pharmacology, 2015, 283, 187-197. • Nand Lal, Amit Sarswat, Lalit Kumar, Karthik Nandikonda, Santosh Jangir, Veenu Bala, Vishnu Lal Sharma. Synthesis of Dithiocarbamates Containing Disulfide Linkage Using Cyclic Trithiocarbonate and Amines under Solvent–Catalyst Free Condition. Journal of Heterocyclic Chemistry, 2015, 52, 156-162. • Veenu Bala, Santosh Jangir, Dhanaraju Mandalapu, Sonal Gupta, Yashpal S. Chhonker, Nand Lal, Bhavana Kushwaha, Hardik Chandasana, Shagun Krishna, Kavita Rawat, Jagdamba P. Maikhuri, Rabi S. Bhatta, Mohammad I. Siddiqi,Rajkamal Tripathi, Gopal Gupta, Vishnu L. Sharma. Dithiocarbamate- Thiourea Hybrids Useful as Vaginal Microbicides Also Show Reverse Transcriptase Inhibition: Design, Synthesis, Docking and Pharmacokinetic studies. Bioorganic & Medicinal Chemistry Letters, 2015, 25, 881-886. • Gopal Gupta, Santosh Jangir and Vishnu Lal Sharma. Targeting post-ejaculation sperm for value-added contraception. Current Molecular Pharmacology, 2014, 7, 167-174. • Veenu Bala, Santosh Jangir, Vikas Kumar, Dhanaraju Mandalapu, Sonal Gupta, Lalit Kumar, Bhavana Kushwaha, Yashpal S. Chhonker, Atul Krishna, Jagdamba P. Maikhuri, Praveen K. Shukla, Rabi S. Bhatta, Gopal Gupta, Vishnu L. Sharma. Design and synthesis of substituted morpholin/piperidin-1-yl-carbamodithioates as promising vaginal microbicides with spermicidal potential. Bioorganic & Medicinal Chemistry Letters, 2014, 24, 5782-5786. • Veenu Bala, Gopal Gupta, Vishnu Lal Sharma. Chemical and Medicinal Versatility of Dithiocarbamates: An Overview. Mini Review Medicinal Chemistry, 2014, 14, 1021–1032. • Rakesh Kumar Asthana, Rasna Gupta, Nidhi Agrawal, Atul Srivastava, Upma Chaturvedi, Sanjeev Kanojiya, Ashok Kumar Khanna, Gitika Bhatia, Vishnu Lal Sharma. Evaluation of antidyslipidemic effect of mangiferin and amarogentin from swertia chirayita extract in hfd induced charles foster rat model and in vitroantioxidant activity and their docking studies. International Journal of Pharmaceutical Sciences and Research, 2014, 5(9), 3734-3740. • Santosh Jangir, Veenu Bala, Nand Lal, Lalit Kumar, Amit Sarswat, Amit Kumar, Hamidullah, Karan S. Saini, Vikas Sharma, Vikas Verma, Jagdamba P. Maikhuri, Rituraj Konwar, Gopal Gupta, Vishnu L. Sharma. Novel alkylphospholipid-DTC hybrids as promising agents against endocrine related cancers acting via modulation of Akt-pathway. European Journal of Medicinal Chemistry, 2014,85, 638-647. • Hardik Chandasana, Yashpal S. Chhonker, Veenu Bala, Yarra Durga Prasad,Vishnu L. Sharma, Rabi S. Bhatta. A rapid and sensitive LC-MS/MS analysis of diapocynin in rat plasma to investigate in vitro and in vivo pharmacokinetics.Analytical Methods 2014, 6, 7075-82. • Yashpal S. Chhonker, Hardik Chandasanaa, Veenu Bala, Lokesh Kumar,Vishnu Lal Sharma, Gopal Gupta, Rabi S. Bhatta. Quantitative determination of microbicidal spermicide ‘nonoxynol-9’ in rabbit plasma and vaginal fluid using LC–ESI–MS/MS: Application to pharmacokinetic. Journal of Chromatography B, 2014, 965, 127–132. • Mittal M, Khan K, Pal S, Porwal K, China SP, Barbhuyan TK, Bhagel KS, Rawat T, Sanyal S, Bhaduria S, Sharma VL, Chattopadhyay N. The Thiocarbamate Disulphide Drug, Disulfiram Induces Osteopenia in Rats by Inhibition of Osteoblast Function Due to Suppression of Acetaldehyde Dehydrogenase Activity.Toxicological Sciences, 2014, 239, 257-270. • Santosh Jangir, Veenu Bala, Nand Lal, Lalit Kumar, Amit Sarswat, Lokesh Kumar, Bhavana Kushwaha, Pratiksha Singh, Praveen K. Shukla, Jagdamba P. Maikhuri, Gopal Gupta, Vishnu L. Sharma. A unique dithiocarbamate chemistry during design & synthesis of novel sperm-immobilizing agents. Organic & Biomolecular Chemistry, 2014, 12 , 3090-3099. • Amit Anthwal, U. Chinna Rajesh, M.S.M. Rawat, Bhavana Kushwaha, Jagdamba P. Maikhuri, Vishnu L. Sharma, Gopal Gupta, Diwan S. Rawat. Novel metronidazole-chalcone cojugates with potential to counter drug resistance inTrichomona vaginalis. European Journal of Medicinal Chemistry, 2014, 79, 89-94. • Ashish Jain, Lokesh Kumar, Bhavana Kushwaha, Monika Sharma, Aastha Pandey, Vikas Verma, Vikas Sharma, Vishal Singh, Tara Rawat, Vishnu L. Sharma, Jagdamba P. Maikhuri, Gopal Gupta. Combining a synthetic spermicide with a natural trichomonacide for safe, prophylactic contraception. Human Reproduction, 2014, 29, 242-252. • Lalit Kumar, Nand Lal, Vikash Kumar, Amit Sarswat, Santosh Jangir, Veenu Bala, Lokesh Kumar, Bhavana Kushwaha, Atindra K. Pandey, Mohammad I. Siddiqi, Praveen K. Shukla, Jagdamba P. Maikhuri, Gopal Gupta, Vishnu L. Sharma. Azole-carbodithioate hybrids as vaginal anti-Candida contraceptive agents: design, synthesis and docking studies. European Journal of Medicinal Chemistry, 2013,70, 68-77. • Monika Sharma, Lokesh Kumar, Ashish Jain, Vikas Verma, Vikas Sharma, Bhavna Kushwaha, Nand Lal, Lalit Kumar, Tara Rawat, AK Dwivedi, JP Maikhuri, VL Sharma, Gopal Gupta. Designed chemical intervention with thiols for prophylactic contraception. PLOS-One, 2013, 8 (6), page 67365. • Lalit Kumar, Ashish Jain, Nand Lal, Amit Sarswat, Santosh Jangir, Lokesh Kumar, Priyanka Shah, Swatantra K. Jain, Jagdamba P. Maikhuri, Mohammad I. Siddiqi, Gopal Gupta, Vishnu L. Sharma. Potentiating metronidazole scaffold against resistant trichomonas: Design, synthesis, biology and 3D–QSAR analysis. ACS Medicinal Chemistry Letters, 2012, 3 (2), 83-87. • Kumar R, Verma V, Sarswat A, Maikhuri JP, Jain A, Jain RK, Sharma VL, Dalela D, Gupta G. Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms-action of two new agents. Investigational New Drugs, 2012, 30, 582-593. • Ashish Jain, Nand Lal, Lokesh Kumar, Vikas Verma, Rajiv Kumar, Lalit Kumar, Vishal Singh, Raghav K. Mishra, Amit Sarswat, S. K. Jain, J. P. Maikhuri, V. L. Sharma, Gopal Gupta. Novel trichomonacidal spermicides. Antimicrobial Agents and Chemotherapy, 2011, 55 (9), 4343-4351. • Nand Lal, Lalit Kumar, Amit Sarswat, Santosh Jangir, Vishnu Lal Sharma. Synthesis of S-(2-thioxo-1,3-dithiolan-4-yl)methyl-dialkylcarbamothioate and S-thiiran-2-ylmethyl-dialkylcarbamothioate via Intermolecular O−S Rearrangement in Water. Organic Letters, 2011, 13 (9), 2330-2333. • Amit Sarswat, Rajeev Kumar, Lalit Kumar, Nand Lal, Smiriti Sharma, Yenamandra S. Prabhakar, Shailendra K. Pandey, Jawahar Lal, Vikas Verma, Ashish Jain, Jagdamba P. Maikhuri, Diwakar Dalela, Kirti, Gopal Gupta, Vishnu L. Sharma. Arylpiperazines for Management of Benign Prostatic Hyperplasia: Design, Synthesis, Quantative Structure – Activity Relationships, and Parmacokinetic Studies. Journal of Medicinal Chemistry, 2011, 54 (1), 302-311. • Lalit Kumar, Amit Sarswat, Nand Lal, Ashish Jain, Sumit Kumar, S.T.V.S. Kiran Kumar, Jagdamba P. Maikhuri, Atindra K. Pandey, Praveen K. Shukla, Gopal Gupta, Vishnu L. Sharma. Design and Synthesis of 3-(azol-1-yl)phenylprapanes as spermicide for prophylactic contraception . Bioorganic & Medicinal Chemistry Letters, 2011, 21(1), 176-181.
LIST OF PATENTS
1 Kalpana Bhandari, V.L. Sharma and S. Ray. “An improved process for the synthesis of 3,4-disubstituted-1,5-dihydro-2H-3-pyrrolin-2-one” Indian PatentAppl. 323/Del/01 dt 23.3.2001. 2 A.K.Dwivedi, V.L.Sharma, N.Kumaria, Kiran Kumar, G.Gupta, J.P.Maikhuri, J.D.Dhar, Pradeep Kumar, A.H.Ansari, P.K.Shukla, M.Kumar, Raja Roy , K.P.Madhusudanan, R.C.Gupta, Pratima Srivastava, R.Pal, and S.Singh. “Novel spermicidal and antifungal agents” Indian Patent 245815 dt 25.01.2011 ; Appl. No.1792/Del/04 dt 22.09.2004. 3 Vishanu Lal Sharma, Nand Lal, Amit Sarswat, Santosh Jangir, Veenu Bala, Lalit Kumar, Tara Rawat, Ashish Jain, Lokesh Kumar, Jagdamba Prasad Maikhuri, Gopal Gupta. “ Carbodithioates and process for preparation thereof ” NF No. 0030/NF2013/IN, Indian Patent Appl. no.0373/DEL/2013 dated 08.02.2013. 4 Vishanu Lal Sharma, Nand Lal, Amit Sarswat, Santosh Jangir, Veenu Bala, Lalit Kumar, Tara Rawat, Ashish Jain, Lokesh Kumar, Jagdamba Prasad Maikhuri, Gopal Gupta, “ Carbodithioates with spermicidal activity and process for preparation thereof ” PCT Patent no. WO 2014122670 August 14, 2014. 5 Dhanaraju Mandalapu, Rajesh K. Arigela, Tara Rawat, and Vishnu L. Sharma, “An Improved Process For Preparation Of 4-Substituted amino-2,3-polymethylenequinoline hydrochloride ” Indian Patent IN 201611003055 dated: 28.01.2016.

From left to right upper row: Dr. S.T.V.S. Kiran Kumar, Dr. Lalit Kumar, Dr. V.L. Sharma, Dr. Nand Lal, Dr. Amit Sarswat
Lower row: Dhanaraju Mandalapu, Sonal Gupta, Mrs. Tara Rawat (S.T.O.), Dr. Veenu bala, Dr. Santosh Jangir

///////////aryl piperazine, androgen sensitive prostatic disorders, 330633-91-5, CDRI-?

c1(ccc(cc1)[N+]([O-])=O)N2CCN(CC2)C(=O)CN3CCN(CC3)c4ccc(cc4)[N+]([O-])=O