Dr. Sandip B. Bharate

Medicinal Chemistry Division
CSIR - Indian Institute of Integrative Medicine,Canal Road, Jammu – 180001
Email: sbharate@iiim.ac.in

Positions Held  
Position Held Date Organization
Senior Scientist 2012 - Present CSIR-IIIM
Scientist Fellow 2011 - 2012 CSIR-IIIM
Postdoctoral Scientist 2008 - 2010 University of Montana, USA
Research Scientist 2007 - 2008 Nicholas Piramal Research Centre, Mumbai
Research Chemist 2003-2003 Dr Reddy’s Laboratories Limited, Hyderabad
Honours & Awards  
  • CSIR-Young Scientist Award (2016) in Chemical Sciences

  • NASI-Young Scientist Platinum Jubilee Award (2015) in Chemical Sciences

  • RSC - OSDD Ambassador Award 2014

  • DST Fast-track grant for Young Scientists (2013-2016)

  • Winner of Innocentive Awards (2009-2010) - Five awards

  • Winner of 2009 Top Solver Award from Innocentive Team

  • Best presentation award for oral presentation at ISMAS-WS 2004, Shimla, India in October, 2004

  • Qualified GATE-2001 (Pharmaceutical Sciences) with 98.78 percentile (All India Rank: 041).

  • Award of a research fellowship from NIPER during M.S. Pharm. (2001-2002) and Ph.D. (2003-2006)

Membership  
  • Associate Member of Royal Society of Chemistry (RSC)

  • Member of American Chemical Society (2010-2011)

  • Life member of Maharashtra State Pharmacy Council

  • Life member of Indian Society for Mass Spectrometry (ISMAS)

  • Reviewer forJournal of Medicinal Chemistry, ACS Medicinal Chemistry Letters, RSC Advances, Chemical Communications, European Journal of Medicinal Chemistry, Bioorganic & Medicinal Chemistry, Bioorganic & Medicinal Chemistry Letters, Medicinal Chemistry Research, Food and Chemical Toxicology, Expert Opinion on Drug Metabolism and Toxicology, Mini-Reviews in Medicinal Chemistry, etc.

Research Area

(a). Discovery of disease modifying therapeutics for Alzheimer's disease: 
Alzheimer’s disease (AD) is the most common form of senile dementia and the fourth highest cause of disability and death in the elderly. It is characterized by the presence of three main brain hallmarks viz. diffuse neuronal loss with a particular involvement of the cholinergic system, extracellular protein deposits (amyloid plaques) and intracellular protein deposits (neurofibrillary tangles, NFTs). All current therapies are based on the cholinergic hypothesis and demonstrate only symptomatic treatment. Progression of the disease is not slowed or halted, with symptoms continuing to deteriorate over time. The amyloid-beta clearance occurs primarily via p-glycoprotein efflux pump and several studies have shown that there exists a direct link between P-gp expression and amyloid-beta clearance from brain. These studies were strongly supported by recently published clinical data (Science 2010, 330, 1774), stating that decreased clearance of CNS amyloid-beta is the prime cause of AD. Thus drugs with ability to induce the expression of P-gp (and other transporters located at the bBB) have a great potential to emerge as novel AD therapeutics.

Colupulone and related prenylated phloroglucinol class of natural products are known to activate PXR, and induce P-gp expression, and are reported to show memory enhancement in animal models. Our group is involved in the medicinal chemistry of natural product scaffolds to discover potential amyloid-beta clearance agents. The medicinal chemistry of colupulone and garcinol/ isogarcinol was performed to investigate their potential to increase Aβ clearance across BBB via modulation of efflux pump activity. A colupulone based lead has been identified, which is able to increase the Aβ transport across BBB. Similarly, we have discovered 4-aryl quinoline-2-carboxylate, aryl bisphosphonate ester, and fascaplysin (bis-indole alkaloid) as anti-Alzheimer leads.

(b) Medicinal chemistry of natural products: 

Historically, natural products have been a source of several clinically used drugs. Furthermore, the marine natural products offer an abundant source of pharmacologically active agents with great chemical diversity and complexity, and the potential to produce valuable therapeutic entities. Our group is involved in the medicinal chemistry of natural products (particularly, marine natural products) to explore their therapeutic potential. We apply medicinal chemistry and molecular modeling approach for lead optimization of selected natural product scaffolds. Various interesting natural products derived leads discovered by us are listed below.

(c) Development of domino one-pot approaches for medicinally important compounds:

Development of domino one-pot strategies for synthesis of biologically important scaffolds is of high importance to speed up drug discovery programs. Our research is focused on the development of such protocols for synthesis of medicinally important compounds. Several such protocols have been developed by us (some of them are shown below).

Our group is also interested in employing Diels-Alder Cycloaddition reaction for construction of medicinally important scaffolds. A tandem one-pot multicomponent method for synthesis of flavans has been devised directly from phenolic precursors using perchloric acid supported on silica as a recyclable catalyst. The method involves Knoevenagel-type condensation leading to in-situ formation of transient O-quinone methide, which further undergoes [4+2]-Diels-Alder cycloaddition with styrene to yield flavan skeleton.

We have also established efficient method for ortho-amidoalkylation of phenols via Mannich-type condensation with formaldehyde and lactams. LC-ESI-MS/MS based mechanistic study revealed that reaction proceeds through O-quinone methide (o-QM) and an oxazine intermediate via tandem Knoevenagel condensation, formal [4+2]-Diels-Alder cycloaddition and acid catalyzed oxazine ring opening.

Recently, a new simple and efficient method for the synthesis of 2-phenylnaphthalenes from electron-rich 1-styryl-2-methoxybenzenes has been developed. The reaction proceeds via TFA catalyzed C-C bond cleavage followed by intermolecular [4+2]-Diels-Alder cycloaddition of in situ formed styrenyl trifluoroacetate intermediate.

Publications

Click here for complete list.

  • Sharma, R.; Vishwakarma, R.A.; Bharate, S.B. Ligand-free Cu-Mn spinel oxide catalyzed tandem one-pot C-H amidation and N-arylation of benzyl amines: A facile access to 2-arylquinazolin-4(3H)-ones. Adv. Synth. Catal. (2016), In Press.

  • Bharate, S.B.; Singh, B.; Kachler S.; Oliveira, A.; Kumar, V.; Bharate, S.S.; Vishwakarma, R.A.; Klotz, K.N. Gutiérrez de Terán H. Discovery of 7-(Prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A2A Adenosine Receptor: Prediction from Molecular Modeling. J. Med. Chem. (2016), 59, 5922-5928.

  • Sharma, R.; Patel, N.; Vishwakarma, R.A.; Bharatam, P.V.; Bharate, S.B. Metal-free oxidative cyclization of acetophenones with diamines: A facile access to phenylpyridines. Chem. Commun. (2016), 52, 1009-1012.

  • Mohammed, S.; Vishwakarma, R.A.; Bharate, S.B. Iodine catalyzed oxidative synthesis of quinazolin-4(3H)-ones and pyrazolo[4,3-d]pyrimidin-7(6H)-ones via amination of sp3 C-H bond. J. Org. Chem., 2015, 80, 6915–6921.

  • Mahale, S.; Bharate, S.B.; Manda, S.; Joshi, P.; Jenkins, P.; Vishwakarma, R.A.; Chaudhuri, B. Anti-tumour potential of BPT: A dual inhibitor of Cdk4 and tubulin Polymerization. Cell Death Dis. ( 2015), 6, e1743.

  • Mahale, S.; Bharate, S.B.; Manda, S.; Joshi, P.; Bharate, S.S.; Jenkins, P.R.; Vishwakarma, R.A.; Chaudhuri, B. Biphenyl-4-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-methylamide (CA224), a non-planar analog of fascaplysin inhibits Cdk4 and tubulin polymerization: Evaluation of in vitro and in vivo anticancer activity. J. Med. Chem. (2014), 57, 9658-9672.

  • Mudududdla, R.; Sharma, R.;  Abbat,   S.; Bharatam, P.V.;  Vishwakarma, R.A.; Bharate, S.B. Synthesis of 2-phenylnaphthalenes from styryl-2-methoxybenzenes. Chem. Commun., (2014), 50, 12076-12079.

  • Jain S.K.; Singh, S.; Khajuria, A.; Guru, S.K.; Joshi, P.; Meena, S.; Nadkarni, J.; Singh, A.; Bharate, S.S.; Bhushan, S.; Bharate, S.B.; Vishwakarma, R.A. Pyrano-isochromanones as IL-6 inhibitors: Synthesis, in-vitro and in-vivo anti-arthritic activity. J. Med. Chem. (2014), 57, 7085−7097.

  • Jain, S.K.; Pathania, A.S.; Meena, S.; Sharma, R.; Sharma, A.; Singh, B.; Gupta, B.D.; Bhushan, S.; Bharate, S.B.; Vishwakarma, R.A. Semisynthesis of Mallotus B from Rottlerin: Evaluation of cytotoxicity and apoptosis-inducing activity.  J. Nat. Prod. ( 2013), 76, 1724−1730.

  • Bharate, S.B.; Sawant, S.D.; Singh, P.P.; Vishwakarma, R.A. Kinase inhibitors of marine origin. Chem. Rev.(2013), 113, 6761–6815.

  • Mudududdla, R.; Jain, S.K.; Bharate, J.B.; Gupta, A.P.; Singh, B.; Vishwakarma, R.A.; Bharate, S.B. Ortho-Amidoalkylation of phenols via tandem one-pot approach involving oxazine intermediate. J. Org. Chem. (2012), 77, 8821-8827.

Patents

  • Bharate SB, Singh S, Singh GD, Jain SK, Kumar A, Singh B, Gupta AP, Anand R, Singh A, Kushwaha M, Gupta M, Sharma G, Sharma A, Vishwakarma RA. Standardized extract of Bergenia ciliata for the treatment of inflammatory disorders (IN 201611002826).

  • Bharate SB, Bhushan S, Mohammed S, Guru SK, Bharate SS, Kumar V, Mahajan G, Javed MM, Mondhe DM, Vishwakarma RA. Fused pyrimidines as isoform-selective phosphoinositide-3-kinase-alpha inhibitors and process for preparation thereof. (3818DEL2015).

  • Jain, S.K.; Sidiq, T.; Meena, S.; Khajuria,A.;Vishwakarma, R.A.; Bharate, S.B. Preparation of tetrahydro-2H-pyrano[3,2-c]isochromene-6-one analogs for the treatment of inflammatory disorders. (WO2014188440A1, US20160122360, EP3004116, CA2913281, IN2013DE01565). 

  • Vishwakarma, RA.; Bharate, S.B.; Bhushan, S.; Mondhe, D.M.; Jain, S.K.; Meena ,S.; Guru ,S.K.;Pathania ,A.S.; Kumar. S.;Behl, A.; Mintoo, M.J.; Bharate ,S.S.; Joshi, P. Cyclin-dependent kinase inhibition by 5,7-dihydroxy-8-(3-hydroxy-1-methylpiperidin-4-yl)-2-methyl-4H-chromen-4-one analogs. (WO2014170914A1, US20160052915, EP2986605, CA2908084, IN2013DE01142).

  • Vishwakarma. R.; Jain, S.K.; Bharate ,S.B.; Dar, A.H.; Khajuria .A.;Meena ,S.; Bhola ,S.K.; Qazi ,A.K.; Hussain ,A.; Sidiq ,T.;Shaanker, R.U.;Ravikanth ,G.;Vasudeva, R.;Patel, MK.; Ganeshaiah ,KN. New chromone alkaloid dysoline for the treatment of cancer and inflammatory disorders. (WO2014167580A1, US20160046611, EP2984078, C2909280, IN 2013DE01077).

  • Bharate ,S.B.; Kumar, A.;Manda ,S.; Joshi ,P.; Bharate, S.S.; Wani, A.; Sharma, S.; Vishwakarma, R.A. Alkylidene Phosphonate esters as P-glycoprotein inducers. (WO2016063297A1, 3010DEL2014).

  • Bharate, S.B.; Kumar ,A.; Bharate ,JB.; Joshi, P.; Wani, A.;Mudududdla ,R.;Sharma ,R.;Vishwakarma ,R.A. Polyalkylated acyl and benzoyl-phloroglucinols as potent P-glycoprotein inducers. (WO2016063296A1, 3004DEL2014). 

  • Vishwakarma, R.A.; Bharate ,S.B.; Kumar ,A.; Singh ,B.; Kumar, A.; Bhushan, S.; Hamid ,A.; Joshi ,P.; Guru ,S.K.; Kumar ,S.;Hussain ,A.; Qazi, A.K.; Bharate, S.S.; Sharma, P.; Saxena, A.K.; Mondhe, D.M.;Mahajan ,G.; Wani ,Z. 10-Substituted colchicinoids as potent anticancer agents. (WO2016059650A1, 2929DEL2014).

  • Vishwakarma ,R.A.;  Kumar, A.; Khan, I.A.; Bharate .S.B.; Joshi ,P.; Singh ,S.; Satti, N. A pharmaceutical composition for the treatment of multi-drug resistant infections. (WO2016067309AI, 3077DEL2014).  

  • Bharate, S.B.; Kumar, A.; Manda, S.; Joshi, P.; Bharate, S.S.;Vishwakarma, R.A. N-Substituted beta-carbolinium compounds as potent P-glycoprotein inducers. WO2016063303AAI, 3002DEL2014).

  • Vishwakarma RA, Bharate SB, Bhushan S, Yadav RR, Guru SK, Joshi P. 6-Aryl-4-phenylaminoquinazolines as phosphoinositide 3 kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. (WO2015128873A1, 0554DEL2014).

  • Thompson, C.M.; Bharate ,S.B. Novel benzothiazole-based pyridinium compounds for the treatment or prevention of neurodegenerative diseases or nerve agent exposure. (US20150259336A1).

  • Singh, I.P.;Bhutani,K.K.; Mitra ,D.; Chauthe, S.K.; Bharate ,S.B.;Sabde, S. Novel dimeric phloroglucinol compounds as anti-HIV and microbicidal agents. (1055/DEL/2009).

Current Students

CSIR Fellow
1
Mr. Rohit Sharma (DST Inspire SRF)
2
Mr. Prashant Joshi (CSIR-SRF)
3
Mr. MD Abdullah (UGC-JRF)

Alumni     Thesis Title    
Dr. Ramesh Mudududdla

 

Development of New Metal-Free Protocols for Synthesis of Medicinally Important Scaffolds and Screening of Molecular Libraries for Potential Bioactivities. 2015 Postdoctoral Research Associate, Academia Sinica, Taiwan
Dr. Rammohan R. Yadav Medicinal chemistry of indole and quinazoline class of marine natural products to explore their biological potential 2015 Associate Scientist at GVK Biosciences Hyderabad
Dr. Sudhakar Manda Medicinal chemistry of indole alkaloids and alkylidene phosphonates to explore their biological potential 2015 Senior Research Associate, DRILS Hyderabad
Dr. MD Shabber Design and synthesis of fused pyrimidines as isoform-selective PI3K-alpha inhibitors and development of new synthetic methodologies for carbon-heteroatom bond formation 2015 Assocuate Scientist at GVK Biosciences Hyderabad
 

Dr. Shreyans K. Jain

Isolation, synthetic modifications and biological evaluation of compounds of Dysoxylum binectariferum, Bergenia ciliata and Mallotus philippensis.

2015

Postdoctoral Associate at Georgetown university, USA

Dr. Baljinder Singh Exploring the medicinal potential of high-altitude plants and microbes: Synthesis and biological evaluation of natural products and their analogs 2015 Postdoctoral research associate at Northeastern University, USA
Ms. Rajni Sharma Discovery of natural products based leads for cancer chemoprevention and anticancer therapy via semisynthetic modifications 2016 Research Scientist at Piramal Discovery Solutions Ahmedabad
       

Facilities

  • Semi-preparative HPLC with PDA and ELSD detector

  • Rotary evaporators and vacuum pumps

  • Microplate reader

  • Access available to common instrumentation facility of the institute - NMR, LCMS, FTIR, GC, GCMS, HRMS.

  • Access available to common instruments of the department - Microwave synthesizer, MALDI-TOF