Prof. Bharatam is a medicinal chemist with strong focus on theoretical and synthetic organic chemistry. His work involves rational methods of designing compounds and establishing the experimental proof for the concepts generated using theoretical methods. Members of his research group
(i)	Synthesize compounds with C→N Coordination bonds after design using quantum chemistry
(ii)	Synthesize the computationally designed species to provide proof of the concept
(iii)	Synthesize and biologically evaluate anti-diabetic potential of species
(iv)	Synthesize and biologically evaluate anti-malarial potential of species
(v)	Synthesize and biologically evaluate anti-leishmanial potencial of the species
This group recently identified a novel class of nitrogen species with divalent N(I) state and labelled them as nitreones. Nitreones are ::N(←L)2⊕ species (Chem. Eur. J. 2016, 22, 1088; J. Org. Chem. 2014,79, 4852; J. Phys. Chem. 2011, 115, 7645; Chem. Comm. 2009, 1064) in which the central nitrogen (i) is found in the low oxidation state N(I), (ii) carries two lone pairs of electrons, (iii) forms coordination bonds with electron donating groups like carbenes (iv) isoelectronic to the newly identified carbones, carbon compounds with C(0) oxidation state and (v) low nucloephilicity of nitreones makes them useful as drugs. This novel environment has been identified, analyzed to understand their drug action. Several new compounds were designed and synthesized (Scheme 1). A few of the synthesized guanylthiourea derivatives show anti-malarial activity (in vitro) and one of the compounds has been shown to cure malaria in mouse (in vivo). Anti-diabetic and anti-malarial agents with biguanidine moiety are characterized by nitreone type electronic structure. Metformin, cycloguanil and other related therapeutic agents are the examples of this class of compounds.
		Scheme 1. Reagents and conditions, (% Yield). (a) p-TsOH, i-PrOH, reflux, 5 h (80%), (b) CH3I, TEA, acetone, 42 oC 12 h (60%), (c) P4S10, ethanol, rt, 10 h (65%), (d) CH3I, reflux, 1 h (reaction mixture was directly used in the next step), (e) NH4OAC, MeOH, reflux, 1.5 h (74%).
Compounds with biguanidine structure are effective drugs (metformin for anti-diabetic activity, pyrimethamine for anti-malarial activity). Electronic structure analysis and molecular electronic surface potential analysis (MESP, Fig. 1) showed that the preferred structure is a tautomer of a generally considered structure.		Fig. 1. MESP of biguanide, protonated biguanide and deprotonated biguanide.
Hence, this study provided an opportunity for exploring the biomolecular target for metformin with renewed vision. The protonated and deprotonated states of the systems have been shown to be possessing similar electrostatic surfaces. Further, metformin has been shown to possess, bent allenic character and is isoelectronic to cabodicarbenes. (J. Med. Chem. 2005, 48, 7615; J. Org. Chem. 2011, 76, 2558).
Glitazones produce their insulin sensitivity by acting on the biological target PPARγ (Peroxisome Proliferator Activating Receptors). 3D QSAR (Quantitative Structure Activity Relationships) studies performed on the PPARγ agonists like glitazones, tyrosine derivatives have provided clues for the pharamacophoric properties of this series of compounds. Modulating the pharmacophoric features using the Comparative Molecular Field Analysis (CoMFA) has lead to the design of several new chemical entities with improved therapeutic potential in terms of their predicted IC50 values. This further lead to the work on identifying the pharmacophoric features related to the dual PPARγ and PPARα activity to achieve the synergestic effect of anti-hyperglycemia and anti-triglyceridemia.
Fig. 2 Electrostatic and steric contour map of the molecular fields of dual PPARγ and PPARγ activating agents. The arrows represent the regions of the molecular field which influence the improvement in the PPARα activity (A), PPARγ (G) and dual activity (A+G).		To achieve this goal, a concept of ‘additivity of molecular fields’ was introduced. The steric and electrostatic contour maps (Fig. 2) of the three models have been employed to design new leads with improved therapeutic potential in both PPARγ and PPARα. The newly designed molecules have been validated to be effective compounds by estimating the binding affinity of these systems with the help of molecular docking analysis. The nominee is also involved in carrying out synthesis of theoretically designed compounds to provide proof of concept. Synthesis and radio ligand binding analysis studies provided the proof of concept as 30% of the compounds showed activity, about 10% of them showing better biological activity than the existing drug. (J. Med. Chem. 2005, 48, 3015; Bioorg. Med. Chem. 2007, 15, 1547, Bioorg. Med. Chem. Lett. 2008, 15, 4959). Research work of the Prof. Bharatam in collaborative projects in theoretical organic chemistry and organometallic chemistry also yielded significant results (Chem. Commun. 2003, 1420; Inorg. Chem. 2006, 45, 1535; J. Am. Chem. Soc. 2007, 129, 4506; Angew. Chem. IEE, 2008, 47, 4703, Scientific Reports (Nature), 2016, doi:10.1038/srep20600).