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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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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

Molecular Formula: C22H26N6O5
Molecular Weight: 454.47904 g/mol


CAS 330633-91-5


For treatment of androgen sensitive prostatic disorders


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

Graphical abstract: Design, synthesis and biological profiling of aryl piperazine based scaffolds for the management of androgen sensitive prostatic disorders

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 α1A-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 α1A-blocking activities.

Design, synthesis and biological profiling of aryl piperazine based scaffolds for the management of androgen sensitive prostatic disorders

*Corresponding authors
aMedicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram ext., Lucknow-226031, India
Fax: +91 522 2771941
Tel: +91 522 2772450 Ext. 4671
bEndocrinology Division, CSIR-Central Drug Research Institute, Lucknow-226031, India
cPharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow-226031, India
dMolecular & Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow-226031, India
eAcademy of Scientific and Innovative Research (AcSIR), New Delhi-110001, India
Med. Chem. Commun., 2016, Advance Article

DOI: 10.1039/C6MD00426A,!divAbstract

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.




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

Image result for Medicinal & Process Chemistry Division, CSIR-Central Drug Research InstituteImage result for Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute




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,
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
Research gate
University of Dusseldorf, Dusseldorf, Germany, Oct., 1994 to Dec., 1994
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.
no image
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
Seven (7) students for their Ph.D.
Twenty two (22) students for their Post Graduation degrees
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.
Ms. Mala Singh (2014-2016)
Mr. Dhanaraju Mandalapu (CSIR-SRF; 2012-present)
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)
1. The Uttar Pradesh Association for Advancement of Science, Lucknow (India)
2. Indian Chemical Society (Calcutta)
3. Chemical Research Society of India, (Bangalore)
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.
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
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.
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.


Image result for Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute

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-?



Bulaquine a CDRI India Antimalarial

Figure imgf000005_0001



CAS NO.: 79781-00-3

2(3H)-Furanone, dihydro-3-(1-((4-((6-methoxy-8-quinolinyl)amino)pentyl)amino)ethylidene)-,

 3-[l-[[4-[(6-methoxy-8-quinolinyl)amino]pentyl]amino]- ethyMene]-dihydro-2(3H)furanone

N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine

Aablaquine, Elubaquine, Bulaquine [INN], Compound 80/53, UNII-TSQ6U39Q3G, AC1MI1V2, CHEMBL2106578, CDRI 80/53
Molecular Formula: C21H27N3O3   Molecular Weight: 369.45738




The Central Drug Research Institute has developed an antimalarial Drug – given in house number “Compound 80/53” and allotted International Nonproprietary Name (INN) as Bulaquin – which is a primaquine derivative.

Primaquine is the only drug available for use as anti-relapse, antimalarial for prophylactic in P.vivax malaria. However, this drug causes many side effects and the most commonly cited effect is methaemoglobinaemia in patients with G6PD deficiency. Higher doses of primaquine cause methaemoglobinaemia in most subjects and leukopenia in some. However, there is a small fraction of black population with G6PD deficiency who develop anaemia due to intravascular haemolysis at daily dose levels of 15 mg (base) and above.

It is being increasingly felt that the eroding efficacy of commonly used antimalarials has contributed substantially to the resurgence of malaria during last three decades. Although new antimalarials have appeared in the market during this time, none has yet supplemented chloroquine. There are no drugs in the market or in advanced stages of development that appear to be as well tolerated as chloroquine.

Combinations of existing antimalarials especially those now available in rural clinics and market hold great potential for effective, self-administered therapies for uncomplicated malaria, particularly where relapses are frequently encountered. Applying combined therapies to the problem should demand a high standard of proof of safety and efficacy in randomised double blind, placebo controlled trials.

Bulaquin is without any side effects that have been observed with primaquine. A comparative data analysis on initial (0 day pre-drug) and final (+7 day post-drug) values of haemoglobin, methaemoglobin, prothrombin time, partial thromboplastin time and fibrinogen in healthy human subjects treated with primaquine (15 mg OD x7 days) and Bulaquin (25 mg OD x7 days) have been carried out. The study has shown that one week primaquine treatment leads to rise in methaemoglobin levels from 3.97% to 16.32%, which is highly significant in comparison to the 2.29% and 3.02% levels of methaemoglobin before and after 7 days treatment with Bulaquin respectively. Thus, it is evident that primaquine treatment produces rise in methaemoglobin contrary to Bulaquine does not produce rise in methaemoglobin levels. This result manifests a clear superiority of Bulaquin over Primaquine.

Bulaquin has been licenced to Nicholas Piramal India Ltd., Mumbai for marketing. Nicholas Piramal has introduced Bulaquin alongwith chloroquine into the market as a combination pack under the trade name Aablaquine. The objective of the combined therapy is to control P.vivax malaria more effectively by providing initial cure and thereafter preventing relapses by use of this combination pack. It is hoped that the introduction of this combination pack of Bulaquin should contribute substantially to the ongoing National Malaria action programme advocated by Government of India.

Malaria, caused by a parasitic protozoan called Plasmodium, is one of the most serious and complex tropical parasitic diseases. Generally human malaria is caused by four species of malarial parasites which are Plasmodium falciparwn, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. Of these P. falciparum and P. vivαx are most widespread and cause most of the mortality and morbidity associated with these types of infections.

It is known that the malarial parasites undergo complex life cycle in humans, which is initiated through the bite of an infected female Anopheles mosquito. When the mosquito bites a host, some of the sporozoites are injected into the bloodstream of the host and through the circulation they reach the liver where they multiply and liberate merozoites into the bloodstream which then invade the erythrocytes. In case of infections caused by P. vivαx, most of the time the parasites remain dormant in the liver which stage is termed hypnozoites. Hypnozoites are reactivated and reinitiate blood stage parasitemias causing relapse. It has often been observed that people infected with P. vivax do not experience any symptoms for a very long period after their initial illness but become symptomatic after certain period (Korean J. Intern Med, 1999 Juk 14(2): 86-9).

A number of drugs ranging from those of natural origin to synthetic ones have been developed for the treatment of malaria. Quinine and artemisinin are the commonly known drugs of natural origin, which are mostly used for the treatment of malaria. A number of synthetic anti- malarial drugs such as chloroquine, mefloquine, primaquine, halofantrine, ainodiaquine, proguanil, maloprim are known in the literature. Of all the synthetic anti-malarial agents chloroquine has been the most widely prescribed drug for the treatment of malaria of all the types, for more than last 60 years.

Chloroquine has been the effective treatment so far for the P. vivax malarial infections, however, some strains of P. vivax have shown resistance to this well known drug {Ann. Trop. Med. ParasitoL, 1999 Apr; 93(3): 225-230). In recent years drug resistant malaria has become one of the most serious problems in malaria control. Drug resistance necessitates the use of drugs which are more expensive and may have dangerous side effects. To overcome the problems associated with drug resistance, treatments comprising combinations of anti-malarial agents are on the rise. A number of anti-malarial combinations are already known in the malarial chemotherapy. For example, a combination of amodiaquine and tetracycline, a combination of sulfadoxine and pyrimethamine known as fansidar, are known therapies for the treatment of P. falάparum. Also fansimef, a combination of mefloquine with sulfadoxine and pyrimetha min e is used against multidrug resistant strains of P. faldparum.

United States Patent No. 5 998 449 describes a method for the treatment of malaria wherein combination of atovaquone and proguanil is used for the treatment of malaria. In US Patent No. 5 834 505, combination of fenozan with another anti-malarial agent selected from artemisinin, sodium artesunate, chloroquine, mefloquine is described for the prophylactic and curative treatment of malaria.

All the aforementioned anti-malarial combinations reported heretofore are generally used for the treatment of P. faldparum. None of the standard anti-malarial combination treatment regimens have been found to be favourable for the treatment of P. vivax malaria which is the most relapsing type of malaria. For a very long time chloroquine was used for the treatment of infections caused by P. vivax, however, chloroquine eradicates only the asexual erythrocytic stages of P. vivax and does not eliminate the hypnozoites. Until recently primaquine has been the drug of choice for the treatment of malarial relapse. Generally the standard therapy for the P. vivax malarial infection comprises of a sequential chloroquine-primaquine combination treatment regimen wherein primaquine is administered for 14 days following the 3 days course of chloroquine. WHO (World Health Organisation) also recommends a 14 days primaquine treatment for P. vivax malarial infection. A shorter duration of cMoroquine-primaquine treatment regimen was also tried out wherein primaquine was administered only for 5 days following the chloroquine course. However, the outcome of the treatment was not encouraging, since the percentage relapse was more than the standard 14 days primaquine treatment regimen (Trans. R. Soc. Trop. Med. Hyg., 93(6), 641-643). Also primaquine is known to cause hemolytic anemia in persons deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) (Pharmacol Rev. 21: 73-103 (1969); Rev. Cubana Med trop, 1997; 49 (2): 136-8 ). Moreover, methemoglobin toxicity is another predictable dose-related adverse effect associated with primaquine. Needless to say that in the case of sequential combination therapy the patient may not complete the course once the symptoms of malaria are diminished, hence this may increase the chances of relapse. Thus, the chloroquine- primaquine treatment regimen is not safe with respect to toxicity of primaquine and has a further limitation from the standpoint of patient compliance due to longer duration of treatment.

Another anti-relapse agent namely tafenoquine is disclosed in United States Patent 4 617 394. Though more effective than primaquine, the drug was found to cause methemoglobin toxicity almost three times more than that of primaqu ie (Fundam. Appl. Toxicol. 1988, 10(2), 270-275), hence has drawbacks in terms of safety.

The compound, 3-[l-[[4-[(6-nιethoxy-8-quinolinyl)aιnino]pentyl)am.ino]- ethylidene]-dihydro-2(3H)furanone is a derivative of primaquine. It was described in Indian Patent Specification No. 158111 as 6-methoxy-8-(4-

N-(3′-aceto-4^5′-dihydro-2-furanylamino)- l-methylbutylamino)quinoline , the structure of which was revised to that represented by the following formula I. As per the revised structure, the compound is named 3-[l-[[4-

[(6-metJhoxy-8-quinolmyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)- furanone (hereinafter referred to as compound I). The revised structure is described in WHO Drug Information Vol. 13, No. 4, pg. 268 (1999).

Figure imgf000005_0001

The compound of formula (I) has been found to be safer and less toxic than the parent compound primaquine (Am. J. Trop. Med. Hyg, 1989 Dec; 41(6): 635-637). Its anti-relapse activity has been found to be comparable to primaquine.

Over the years primaquine was the only drug used for the radical cure of malaria caused by P. vivax. Primaquine is associated with a number of severe adverse effects, therefore there is a need to develop agents which are more effective and/ or less toxic than primaquine. The compound I has been found to exhibit anti-relapse activity comparable to Primaquine (Am. J. Trop. Med. Hyg., 41(6): 633-637 (1989)). However, this compound has been shown to cause less methemoglobin formation (Am. J. Trop Hyg., 41(6): 638-642 (1989) ) and also has less effect on anti-oxidant defence enzymes than primaquine (Biochem Pharmacol. 46(10): 1859- 1860 (1993) ). Thus, this primaquine derivative (I) is found to be less toxic as compared to the parent drug, primaquine.

Therefore, there is a longfelt need for a more practical, effective, patient compliant and safe remedy for the radical cure of P. vivax malarial infection.

The inventors have found that the longfelt need may be fulfilled by providing a treatment regimen consisting of regulated use of chloroquine and 3-[l-[[4-[(6-methoxy-8-quinolinyl)aιnino]pentyl]amino]ethylidene]- dihydro-2(3H)furanone of formula I over a period of between 5 to 8 days.

It has also been found that the treatment regimen may be executed most effectively and in a user friendly manner by providing a combination kit which comprises two anti-malarial agents, namely chloroquine and 3-[l- [[4-[(6-meth.oxy-8-qumolmyl)am^


The title enamine derivative is prepared by condensation of primaquine (I) with acetyl butyrolactone (II) by means of piperidine.


  • manufacture fo a medicament for the treatment of malaria of primaquine derivative N1-(3-ethylidinotetrahydrofuran-2-one)-N4-(6-methoxy-8-quinolinyl)-1,4-pentanediamine as a gametocytocidal agent. More particularly, this invention relates to the use of primaquine derivative N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine of formula 1 shown below useful for controlling the spread of malaria by virtue of its high therapeutic value as a gametocytocidal agent.
Figure 00010001
    • The primaquine derivative of the present invention does not damage either normal or G-6PD deficient erythrocytes to the extent it is observed with the use of primaquine.
      • scheme:

        Figure 00150001

The following example illustrates the details of the process of this invention:

N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine

  • A mixture of primaquine base (0.97g, 3.7 mmole) freshly distilled 3-acetyl-r-butyrolactone (1.0g, 7.8 mmole) and a base like piperidine (2-3 drops) were stirred under magnetic stirrer at room temperature. In an hour or so the reaction mixture solidified. The product was titrated in ether and filtered to get the product. It was crystallised from alcoholic solvent like propanol. Yield 0.89g, m.p. 118-120°C.


BELL A.: “Recent developments in the chemotherapy of malaria.” CURRENT OPINION IN ANTI-INFECTIVE INVESTIGATIONAL DRUGS, (2000) 2/1 (63-70). , XP001038054
2 * DUTTA, G. P. ET AL: “Radical curative activity of a new 8-aminoquinoline derivative ( CDRI 80/53) against Plasmodium cynomolgi B in monkeys” AM. J. TROP. MED. HYG. (1989), 41(6), 635-7 , 1989, XP001037488 cited in the application
3 * KAR, K. ET AL: “Pharmacology of compound CDRI 80/53;a potential new antirelapse antimalarial agent” INDIAN J. PARASITOL. (1988), 12, 259-62 , 1988, XP001034143
4 * NEWTON P. ET AL: “Malaria: New developments in treatment and prevention.” ANNUAL REVIEW OF MEDICINE, (1999) 50/- (179-192). , XP001036946
5 * PALIWAL, JYOTI KUMAR ET AL: “Simultaneous determination of a new antimalarial agent, CDRI compound 80/53, and its metabolite primaquine in serum by high-performance liquid chromatography” J. CHROMATOGR., BIOMED. APPL. (1993), 616(1), 155-60 , 1993, XP000955186
6 * PURI, S. K. ET AL: “Methemoglobin toxicity and hematological studies on malaria anti-relapse compound CDRI 80/53 in dogs” AM. J. TROP. MED. HYG. (1989), 41(6), 638-42 , 1989, XP001037486 cited in the application
7 * SETHI, N. ET AL: “Long term toxicity studies with a synthetic anti-relapse antimalarial compound 80/53 in rats and monkeys” INDIAN J. PARASITOL. (1993), 17(1), 15-26 , 1993, XP001034142
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CDRI planning to launch Phase-1 trials on 2 candidate drugs to fight malaria, diabetes





CDRI planning to launch Phase-1 trials on 2 candidate drugs to fight malaria, diabetes

The Central Drug Research Institute (CDRI), the public sector premier institution for drug discovery, will soon start Phase 1 clinical trials of a candidate …

Joseph Alexander, New Delhi
Monday, April 14, 2014, 08:00 Hrs  [IST]

The Central Drug Research Institute (CDRI), the public sector premier institution for drug discovery, will soon start Phase 1 clinical trials of a candidate drug against malaria and another one to fight diabetes.

The institute has developed and licensed the anti-hyperglycemic candidate drug (CDR134F194) to TVC Sky Shop Ltd., Mumbai. The process of formulation of the drug in a GMP certified company is in progress. The single dose and multi-dose Phase- I clinical trial will be initiated soon at KEM Hospital & Seth GS Medical College in Mumbai. The permission for the trials was already given by the Drugs Controller General of India (DCGI), sources said.

Another candidate drug developed by the CDRI and waiting for the trials is in the therapeutic area of malaria. The single dose pharmacokinetic study in healthy volunteers as per revised protocol approved by DCGI was completed at PGIMER, Chandigarh for the CDRI compound 97/78 (Anti-malarial agent).  A total of 16 volunteers completed the trial. The blood samples were analysed inthe Pharmacokinetics & Metabolism division and the final report on single dose pharmacokinetic study submitted to IPCA, Mumbai.


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