Dr. Sandip B. Bharate

Medicinal Chemistry Division
CSIR - Indian Institute of Integrative Medicine,Canal Road, Jammu – 180001
Email: sbharate[at]iiim[dot]ac[dot]in

Positions Held  
Position Held Date Organization
Principal Scientist 2015-Present CSIR - IIIM Jammu
Senior Scientist 2012-2015 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 for Journal 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.


Technologies developed/ transferred

IIIM-141 - Discovered, developed, and Out-licensed Saffron-based anti-Alzheimer lead IIIM-141 to M/S Pharmanza Herbals Pvt Ltd Gujarat for launching it as a nutraceutical product.

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.

  • Abdullaha, M.; Mohammed, S.; Ali M; K.A; Vishwakarma ,R.A;  Bharate ,S.B. Discovery of Quinazolin-4(3H)-ones as NLRP3 Inflammasome Inhibitors: Computational Design, Metal-free Synthesis and In-vitro Biological Evaluation. J. Org. Chem. 2019, DOI: 10.1021/acs.joc.9b00138.

  • Bharate, S.B.; Kumar, V.; Bharate, S.S.; Singh, B.; Singh, G.D.; Singh, A.; Gupta, M.; Singh, D.; Kumar, A.; Singh S.; Vishwakarma, R.A. Discovery and Preclinical Development of IIIM-160, Bergenia ciliata Based Anti-inflammatory and Anti-arthritic Botanical Drug Candidate. J. Integr. Med. 2019, https://doi.org/10.1016/j.joim.2019.03.001.

  • Bharate, S.S.; Kumar, V.; Singh, G.D.; Singh, A.; Gupta, M.; Singh, D.; Kumar, A.; Vishwakarma, R.A.; Bharate, SB. Preclinical development of Crocus sativus based botanical lead IIIM-141 for Alzheimer's disease: Chemical standardization, efficacy, formulation development, pharmacokinetics and safety pharmacology. ACS Omega, 2018, 3, 9572−9585.

  • Mudududdla, R..; Mohanakrishnan, D.; Bharate, S.S.; Vishwakarma, R.A.; Sahal, D.; Bharate, S.B. Orally Effective Aminoalkyl 10H-Indolo-[3,2-b]quinoline-11-carboxamide Kills the Malaria Parasite by Inhibiting Host Hemoglobin Uptake. ChemMedChem,2018, 13, 2581-2598.

  • Bharate, S.B; Kumar ,V.; Jain, S.K.; Mintoo, N.J.; Guru ,S.K.; Nuthakki, V.K,.; Sharma, M.; Bharate, S.S.; Gandhi, S.G.; Mondhe, D.M.; Bhushan, S.; Vishwakarma ,R.A. Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-dependent Kinase Inhibitor. J. Med. Chem. 2018, 61, 1664-1687.

  • Sharma, R.; Abdullaha ,M.; Bharate S.B. Oxidant-Controlled C-sp2/sp3 – H Cross-dehydrogenative Coupling of N-Heterocycles with Benzylamines. J. Org. Chem. 2017, 82, 9786–9793.

  • Joshi, P.; McCann, G.J.P.; Sonawane, V.R.; Vishwakarma, R.A.; Chaudhuri, B.; Bharate, S.B.* Identification of Potent and Selective CYP1A1 Inhibitors via Combined Ligand and Structure-Based Virtual Screening and Their in Vitro Validation in Sacchrosomes and Live Human Cells. J. Chem. Inform. Model. 2017, 57, 1309–1320.

  • 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.; 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.

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

Patents

  • Bharate, SB.; 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, EPEP3209671)

  • Bharate, S.B.; Kumar, A.; Bharate, J.B.; Joshi, P.; Wani ,A.; Mudududdla ,R.; Sharma, R.; Vishwakarma ,R.A. Polyalkylated acyl and benzoyl-phloroglucinols as potent P-glycoprotein inducers. (WO2016063296A1, 3004DEL2014, US10202326B2)

  • Vishwakarma, R.A.; 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, US9932327B2, EP2986605)

  • 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, 1565DEL2013 Granted in US, EPUS9777014B2, 2017, EP 3004116, 2018)

  • 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.; Uma, S.R.; Ravikanth, G.; Vasudeva ,R.; Patel ,M.K.; Ganeshaiah, K.N. New chromone alkaloid dysoline for the treatment of cancer and inflammatory disorders. (IN2013DE01077A, WO2014167580A1, EPUS9776989B2, EP 2984078)

  • 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, US9868695, EP3207026)

  • 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. (WO2016067309A1, 3077DEL2014, EPEP15807704.0)

  • Vishwakarma, R.A.; Bharate ,S.B.; Bhushan, S.; Yadav ,R.R.; Guru, S.K.; 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, EP3110801B1)

  • Bharate, S.B.; Bhushan ,S.; Mohammed, S.; Guru, S.K.; Bharate, S.S.; Kumar, V.; Mahajan ,G.; Javed,  M.M.; Mondhe ,D.M,.; Vishwakarma, R.A. Fused pyrimidines as isoform-selective phosphoinositide-3-kinase-alpha inhibitors and process for preparation thereof. (WO2017090058A1, 3818DEL2015)

  • 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. (WO2016063303A1, 3002DEL2014)

  • Thompson, C.M.; Bharate, S.B. Benzothiazole-based pyridinium compounds. (US20150259336A1, US US9255091B2)

  • 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)

  • Bharate, S.B.; Sharma ,R.; Joshi ,P.; Vishwakarma ,R.A.; Chaudhuri ,B. Furanochalcones and furanoflavones as inhibitors of CYP1A1, CYP1A2 and CYP1B1 for cancer chemoprevention. (IN201611027579, WO2018029710)

  • Bharate ,S.S.; Kumar ,V.; Singh ,R.; Rani, S.; Gupta ,M.; Kumar, A.; Bharate, S.B.; Vishwakarma, R.A. Sustained release formulations of Crocus sativus. (IN201711036084, PCT/IN2018/050629)

  • Bharate, S.S.; Singh ,R.; Gupta ,M.; Singh. B.; Katare, A.K.; Kumar, A.; Bharate, S.B.; Vishwakarma, R.A. Gastroretentive sustained release formulations of Bergenia ciliata. (IN201711036683, PCT/IN2018/050588)

  • Bharate ,S.S.; Kumar, V.; Gupta, M.; Gandhi ,S.; Kumar ,A.; Bharate, S.B.; Vishwakarma ,R.A. Sustained release formulations of Dysoxylum binectariferum. (IN201811014818)

  • Bharate, S.S.; Kumar, V.; Mintoo, M.J.; Mondhe, D.M.; Bharate, S.B.; Vishwakarma ,R.A. Novel oral formulation of anticancer compound with improved efficacy.( IN201811026240)

Current Students

PhD Students
1
Mohd. Abdullaha (UGC-SRF) (2016-Present)
2
Rinky Raghuvanshi (UGC-JRF) (2018-Present)
   
Project Fellows
1
Vijay Nuthakki, Project Assistant II (November 2016-Present)
2
Mohit Sharma, Project Assistant II (May 2017-Present)
3
Ankita Sharma, Project Assistant II (August 2017-Present)
4
Deendyal Bhurta, Project Assistant II (September 2017-Present)

Alumni     Thesis Title Year
Ramesh Mudududdla

 

Development of New Metal-Free Protocols for Synthesis of Medicinally Important Scaffolds and Screening of Molecular Libraries for Potential Bioactivities; AcSIR-IIIM. 2015
Rammohan R. Yadav Medicinal chemistry of indole and quinazoline class of marine natural products to explore their biological potential; AcSIR-IIIM. 2015
Sudhakar Manda Medicinal chemistry of indole alkaloids and alkylidene phosphonates to explore their biological potential; AcSIR-IIIM. 2015
Rohit Sharma Oxidative reactions for C-C and C-N bond formation involving aliphatic amines and amides; AcSIR-IIIM. 2017
Prashant Joshi Computational approaches for identification and optimization of new leads for cancer and infection; AcSIR-IIIM. 2017
 

Shreyans K. Jain

Isolation, synthetic modifications and biological evaluation of compounds of Dysoxylum binectariferum, Bergenia ciliata and Mallotus philippensis; AcSIR-IIIM (co-supervisor)

2015
Baljinder Singh Exploring the medicinal potential of high-altitude plants and microbes: Synthesis and biological evaluation of natural products and their analogs; AcSIR-IIIM (co-supervisor) 2015
Mohd Shabber Design and synthesis of fused pyrimidines as isoform-selective PI3K-alpha inhibitors and development of new synthetic methodologies for carbon-heteroatom bond formation; AcSIR-IIIM (co-supervisor) 2015
Rajni Sharma Discovery of natural products based leads for cancer chemoprevention and anticancer therapy via semisynthetic modifications; AcSIR-IIIM (co-supervisor) 2016

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