Project proposal

Studies on designing, syntheses, characterization, and
biological screening of organic cocrystals
Preamble:
Organic cocrystals are at the forefront of the quest for novel crystal forms. There is a strong interest in their potential use in the pharmaceutical field and in all areas where the final products are commercialized and utilized in their solid state forms. Cocrystals are intensively investigated for mechanism of recognition, packing, and assembly. The hierarchy of the supramolecular synthons that can occur for a range of common functional groups in order to design new cocrystals and certain functional groups such as carboxylic acids, amides, and alcohols are particularly amenable to formation of supramolecular heterosynthons (i.e. non-covalent bonds between different but complementary functional groups). It is becoming evident that such interactions are the key to implementing a design strategy for cocrystals in which a target molecule forms cocrystals with a series of cocrystal formers that are carefully selected for their ability to form supramolecular heterosynthons with the target molecule. Cocrystals involving these supramolecular synthons can be synthesized by slow evaporation from a solution containing stoichiometric amounts of the components (cocrystal formers); however, sublimation, growth from the melt, or grinding of two or more solid cocrystal formers in a ball mill are also suitable methodologies. Issues of focus:
Most recently, in the field of pharmaceuticals, cocrystallization has been shown to be an effective means of altering a drug’s physical properties, such as stability, solubility, bioactivity, moisture uptake, melting point etc.[1]. Cocrystals offer opportunities to modify the composition of matter and the chemical and/or physical properties of a molecular species without the need to make or break covalent bonds. Solid-state synthesis offers great potential in the context of green chemistry (high yield, regio/stereospecificity, no solvent or by-products). There is now a catalog of research that demonstrates how non-covalent interactions [2] or coordination bonds [3] can afford control over alignment of reactants and topochemistry. Combination of different compounds may lead to be an effective drug. Reference
[1] (a) J.F. Remenar, S.L. Morissette, M.L. Peterson, B. Moulton, J.M. MacPhee, H.R.
Guzmán, Ö. Almarsson, J. Am. Chem. Soc. 125 (2003) 8456; (b) R.D. Bailey Walsh,
M.W. Bradner, S. Fleischman, L.A. Morales, B. Moulton, N.R. Hornedo, M.J.
Zaworotko, Chem. Comm. (2003)186.
[2] MacGillivray, L.R. et al. (2000) Supramolecular control of reactivity in the solid state using linear molecular templates. J. Am. Chem. Soc. 122, 7817–7818 [3] Toh, N.L. et al. (2005) Topochemical photodimerization in the coordination polymer [{(CF3CO2)(mu-O2CCH3)Zn)(2)(mu-bpe)(2)](n) through single-crystal to single-crystal transformation. Angew. Chem. Int. Ed. 44, 2237–2241. Objective/Research Focus:
1.
To synthesize cocrystals from bioactive carboxylic acids synthesized in our laboratory with bioactive amines/amides such as caffeine, theophylline, theobromine, thiamin, isonicotinamide, 4-chlorobenzamide, maleic hydrazide, gabapentin, ranitidine, metformin etc. 2. To characterize these cocrystals using FT-IR, NMR, PXRD, single crystal XRD, To study the minimum energy of cocrystals by Gaussian method (DFT). To study their biological properties such as antimicrobial activity, antioxidant activity, antituberculosis activity etc. Reasons and Justification:
The aryloxyaliphatic acids and the pyrazolecarboxylic acids synthesized in our laboratory show bioactivity towards antimicrobial activity, antioxidant activity, antituberculosis activity, anticancer activity etc. Some of these compounds display better activity than the standard drugs used for comparison. Hence we were mooted to undertake this project. It also will help us to understand whether a combination of these compounds would act as a drug and could get commercialized. Deliverable:
Aryloxyaliphatic acids, phenolic acids, and a series of pyrazolecarboxylic acids synthesized in our laboratory are found to be bioactive. Hence these acids will be used to make cocrystals with bioactive amines/amides such as caffeine, theophylline, theobromine, thiamin, isonicotinamide, 4-chlorobenzamide, maleichydrazide, gabapentin, ranitidine, metformin etc.
Work plan:
1.
Syntheses of various aryloxyaliphatic acids and pyrazolecarboxylic acids. Syntheses of cocrystals of these acids with different bioactive amines/amides. Theoretical studies of new cocrystals (DFT). Biological screening of new cocrystals. Aryloxyaliphatic acids, phenolic acids, and a series of pyrazole carboxylic acids synthesized in our laboratory are found to be bioactive. Hence these acids will be used to make cocrystals with bioactive amines/amides such as caffeine, theophylline, theobromine, thiamin, isonicotinamide, 4-chlorobenzamide, maleichydrazide, gabapentin, ranitidine, metformin etc. Crystallization techniques such as slow evaporation, solvent-drop grinding, solid- solid synthesis etc will be followed. The cocrystals obtained will be characterized by spectral means, single crystal XRD, PXRD, TGA/DTA. The stability of the cocrystals will be studied by computational methods (DFT) using Gaussian software. Biological activities of these cocrystals will be studied. H-bonding and pi-pi interaction motifs will also be studied. Aryloxyacetic acid derivatives possess antimicrobial-, antioxidant-, antibacterial-, analgesic-, antisickling-, antiplatet-, non-prostacyclin mimetic-, and diuretic activities, and they serve as growth regulators. Several synthetic applications of pyrazolecarboxylic acids were reported recently including their use in the synthesis of potential drugs for Alzheimer’s disease, cerebral apoplexy, manic-depressive illness, schizophrenia, cancer, type II diabetes and obesity, antitussive and antiemetic activity, analgesics, anti-depressives, antipyretics, herbicideal and insecticideal activities. Gabapentin is a pharmaceutical drug used in the treatment of epilepsy and also used to relieve neuropathic pain. Ranitidine is commonly used in the treatment of peptic ulcers. Metformin is an oral antihyperglycemic drug used in the management of type 2 diabetes. The proposer will be coordinating with Prof. P. Thomas Muthiah, Head, Dept of Chemistry, Bharathidasan University, Tiruchirappalli, TN and Prof. P. Kumaradhas, Dept of Physics, Periyar University, Salem, TN for crystallographic studies. Program Schedule, including Activity Diagram/Bar Chart:
Year-wise plan of work and targets to be achieved:
Research Activity
Procuring chemicals, glassware – literature survey – purification and drying of solvents etc and similar preliminary works, Selection and appointment of JRF. Syntheses and Characterization of cocrystals using IR, PMR, CMR, Mass, single Syntheses and Characterization of cocrystals using IR, PMR, CMR, Mass, single Syntheses and Characterization of cocrystals using IR, PMR, CMR, Mass, single Syntheses and Characterization of cocrystals using IR, PMR, CMR, Mass, single Biological evaluation of newly synthesized cocrystals Preparation and submission of project report.
Proposed budget

Description
Sub Total
Contigency
Equipment
(itemwise)
Total cost of the
Outcomes & outputs
1. Stability of the cocrystals formed will be understood through their TGA/DTA, 2. The H-bonding and pi-pi interactions present can provide valuable information about the assembly of these cocrystals. 3. Consequences of the H-bonding in the cocrystals can be correlated with the IR 4. Cocrystals showing useful bioactivity may become commercially important List of Last Five Years Publication (2007-2012)

1.
R. Ramasubramanian, S. Kumaresan, R. Thomas, A. David Stephen and P.Kumaradhas, “Synthesis and crystal structure investigation of pyridine-2-(3′-9-
mercaptopropanoic acid)-N-oxide”, (2007), Cryst. Res. Technol., 42(10) 1024-1028.
2.
R. Ramasubramanian, S. Kumaresan, B. Sridhar, A. David Stephen and P.Kumaradhas, “meso-1,2-Diphenylethylenediammoniumbis(squarate)”, (2007) Acta
Cryst., E63, o3034-o3035.
3.
Murugan Indrani, Sudalaiandi Kumaresan, Ramasamy Ramasubramanian, and Manuel Soriano-García, “Synthesis and Single Crystal Structural Characterization of
Hexaaquacobalt(II) 1-oxopyridinium-2-thiopropionate”, (2007), Analytical Sciences, 23,
x127-x128.
Ramasamy Ramasubramanian, Sudalaiandi Kumaresan, Murugan Indrani, Arputharaj David Stephen, Poomani Kumaradhas, Reji thomas, and Bahlul Z. Awen,
“Crystal
Poly[diaquabarium(II)-µ-aqua-κ2Ο:Ο-di-µ-1- oxopyridinium-2-thioacetato-κ4 Ο:Ο trihydrate]”, (2007), Analytical Sciences,23, x149-
x150.
5.
Ramasamy Ramasubramanian, Murugan Indrani, Sudalaiandi Kumaresan, Frank R. Fronczek and Bahlul Z. Awen, “meso-1,2-Diphenylethylenediammoniumadipate”,
(2007), Acta Cryst., E63, o3800.
6.
William T. A. Harrison, Palani Ramadevi, P. G. Seethalakshmi and Sudalaiandi Kumaresan, “4-Aza-1-azoniabicyclo[2.2.2]octane eosinide” (2007), Acta Cryst., E63,
o3911.
7.
S. Kumaresan, R. Jothibai Margret and G. Indra Jasmine, “Chloroperoxidase
activity in some marine algae from Tuticorin coast of Tamilnadu”, (2007), Seaweed Res.
Utiln., 1&2, 63-66.
8.
S. Kumaresan, R. Jothibai Margret and G. Indra Jasmine, “Aminoacid
composition in some marine algae of Tuticorin coast, Tamilnadu”, (2007), Seaweed Res.
Utiln.,1&2, 43-45.
9.
P. G. Seethalakshmi, P. Ramadevi, S. Kumaresan, and W. T. A. Harrison, “1,4- Diazoniabicyclo[2.2.2.]octanebis(3-carboxypyridine-2-carboxylate) (2007), Acta Cryst., E63, o4837.
10.
Murugan Indrani, Ramasamy Ramasubramanian, Sudalaiandi Kumaresan, Mao- Lin Hu and Manuel Soriano-García, “catena- Poly[aqua(1-oxopyridinium-2,10-
thiopropionato-κ1 O1) copper(II)-µ-1-oxopyridinium-2-thiopropionato-κ3 O1: O2: O3
dihydrate]”, (2008), Acta Cryst. C64, m23-m25.
11.
Jothibai Margret , S. Kumaresan, and G. Indra Jasmine, Antimicrobial activities
of some macro alga from the coast of Tuticorin, `Tamilnadu, (2008), R. Seaweed
Research and Utilisation, 30(Special Issue), 149-156.
12.
R .Jothibai Margret, S. Kumaresan, V. R. Mohan, and G. Indra Jasmine, Studies
on biochemical constituents of some macro algae along Tuticorin coast, Tamilnadu.
(2008), Plant Archives, 8(1), 65-68.
13.
R. Ramasubramanian, S. Kumaresan, B. Sridhar, A. David Stephen and P. Kumaradhas, ‘Crystal Structure of a proton transfer self-associated compound:
Tetrakis(guanidinium) bis(eosinate) hexahydrate’, (2008), Analytical Sciences, 24, x243-
x244.
14.
Murugan Indrani, Ramasamy Ramasubramanian, Sudalaiandi Kumaresan, S. K. Kang, Min Chen, and Miao Du, ‘Hydrothermal Synthesis, ‘Crystal structures and
properties of Co(II) and Ni(II) supramolecular complexes with 2,4,6- trimethylenzoate’
(2008), Polyhedron, 27, 3593-3600.
S. Kumaresan, R. Jothibai Margret, V. R. Mohan, Preliminary pharmacognostic studies of Acanthophora spicifera on Tuticorin Coast, Tamilnadu. (2008), J. Medicinal
and Aromatic Plant Sciences, 30, 173.
16.
S. Kumaresan, R. Jothibai Margret , V. R. Mohan,Microscopic and preliminary phytochemical studies on marine algae Padina tetrastromatica and Stoechospermum
marginatum from Tuticorin Coast, Tamilnadu, (2008), Journal of Medicinal and
Aromatic Plant Sciences, 30, 375-380.
17.
R. Jothibai Margret and S. Kumaresan,Infrared and Gas Chromatogram/Mass Spectral Studies on Methanol Extract of Green Alga Ulva Lactuca and Red Alga
Acanthaphora Specifera, (2009), Plant Archives, 9(1), 141-144.
18.
R. Jothibai Margret and S. Kumaresan, Infrared Spectral Studies on Some Marine Macro Algal Benzene Extract, (2009), Plant Archives, 9(1), 227-229.
19.
, R. Jothibai Margret, S. Kumaresan, and S. Ravikumar, A preliminary study on the anti-inflammatory activity of methanol extract of Ulva lactuca in rat (2009), J.
Environmental Biology, 30(5), 899-902.
20.
M. Indrani, R. Ramasubramanian, F. R. Fronczek, N. Y. Vasanthacharya, S. Kumaresan, Self-assembly of three new coordination complexes: Formation of 2-D
square grid, 1-D chain and tape structures, (2009), J. Mol. Struct., 931, 35-44.
21.
Jothibai Margret and S. Kumaresan, ‘Infrared spectral studies of petroleum ether extract of some marine macro algae’, R. (2009), Seaweed Res. Utiln., 31(1&2), 105-108.
22.
M. Indrani, R. Ramasubramanian, S. Kumaresan, F. Fronczek, D. Braga, N. Y. Vasanthacharya,Hydrothermal syntheses, Crystal structures, and antimicrobial activity of
[M(H2O)6] (OPTP)2 where {M=Mg(II), Ni(II), Zn(II); OPTP=1-oxopyridinium-2-
thiopropionato}, (2009), J. Chem. Sci., 121(4), 413-420.
23.
J. Angel Mary Greena, X. Sahaya Shajan and S. Kumaresan, ‘Thermal Studies Pure and Doped Strontium Formate Dihydrate Crystals’, (2010), International Journal
of Materials Science, 5, 209-215.
24.
Jothibai Margret and S. Kumaresan, ‘Preliminary Phytochemical Screening and Infrared Spectral Studies on Chloroform Extract of Some Marine Macro Algae From
Tuticorin Coast, Tamilnadu, India’- Plant Archieves, 10(1), 2010, 97-100.
25.
R. Jothibai Margret and S. Kumaresan, ‘Infrared and Gas Chromatogram/Mass spectral Studies on Padina tetrastromatica Extract’, (2010),Plant Archieves, 10(1), 227-
231.
26.
S. Kumaresan, M. Indrani, R. Ramasubramanian R. Subha, P. Esakki Karthik, S. Athavan, F. R. Fronczek, ‘Syntheses and XRD Characterization of the Organic
Cocrystals, phenylthiopropionic acid:caffeine and benzilic acid:4,4’-bipyridine’, (2010),
International Journal of Current Chemistry, 1(3), 163-174.
27.
R. Jothibai Margret, S. Kumaresan, S. Karthikeyan, Preliminary Phytochemical Screening and Infrared Spectral Studies on Some Extracts of the Marine Macro Algae Sargassum Polycystum and Kappaphycus Alverzii Collected from the Tuticorin coast,
Tamilnadu, India, (2010), Plant Archieves, 10(2), 851-855.
28.
S. Kumaresan and S. John Grant, Studies on the Syntheses, Characterization, Antimicrobial-, Docking-, and DNA Cleaving Ability of Coumarinthioacetic Acid
Derivatives, (2011), International J. Current Chemistry, 2(2), 101-110.
29.
V. Selvaraj, S. Kumaresan and P. Sri Ranganathan, Effect of fluoride and fertilizers on grain yield and fluoride uptake of green gram (Phaseolus mungo), (2011), J.
Ecotoxicol. Environ. Monit. 21(4) 337-340.
30.
R. Jothibai Margret, S. Kumaresan, and V. R. Mohan, Pharmacognostic Studies on Green Alga Caulerpa Scalpelliformis from Tuticorin Coast, Tamilnadu, India, (2011),
Plant Archieves, 11(2), 777-780,.
31.
V. Selvaraj, S. Kumaresan and P. Sri Ranganathan, Effect of fluoride and fertilizers on grain yield and fluoride uptake of green gram (Phaseolus mungo), (2011), J.
Ecotoxicol. Environ. Monit. 21(4) 337-340.
32.
G. S. Suresh Kumar and S. Kumaresan, “Potash Alum [KAl(SO4)2.12H2O] catalyzed esterification of formylphenoxyaliphatic acids” (2012) J. Chem. Sci. 124(4)
857-863.
33.
G. S. Suresh Kumar, S. Kumaresan, C. Shiju, Bijoy Mohan Das, G. Anantharaj, BIS(INDOLYL)METHANES USING KAl(SO4)2·12H2O–ANHYDROUS Na2SO4',
(2012), International Journal of Basic and Applied Chemical Sciences,2 (2), 1-7,.
34.
G. S. Suresh Kumar, S. Kumaresan, A. Antony Muthu Prabu, N, Bhuvanesh, and P.G. Seethalakshmi, An efficient one pot synthesis of aryl-3,3’-bis(indolyl)methanes and
studies on their spectral characteristic, DPPH radical scavenging, antimicrobial,
cytotoxicity, antituberclusis activity, (2012), Spectrochemia Acta part A: Molecular and
Biomolecular Spectroscopy. (DOI - http://dx.doi.org/10.1016/j.saa.2012.09.046).
35.
S. Kumaresan, P. G. Seethalakshmi, P. Kumaradhas, and B. Devipriya, “Synthesis and Structural Characterization of Organic Cocrystals 4,4’-bipyridinium bis(3-carboxypyridine-2-carboxylate)”, J.Mol.
Struct.,
G. S. Suresh Kumar, P. G. Seethalakshmi, N. Bhuvanesh, and S. Kumaresan, “Cocrystals of Caffeine with Formylphenoxyaliphatic Acids: Syntheses, Structural
Characterization, and Biological Activity”, (2012), J. Mol. Struct., DOI-
10.1016/j.molstruct.2012.10.033.
37.
J. Angel Mary Greena, K. Karuppasamy, R. Antony, X. Sahaya Shajan and S. Kumaresan, Stuctural, Thermal and Spectroscopic studies on Zinc Doped Strancium
Formate Dihydrate crystal, IOSR. (2012), J. Appl.Phys., 1 25-28.
38.
J. Angel Mary Greena, K. Karuppasamy, R. Antony, X. Sahaya Shajan and S. Kumaresan, Effect of magnesium doping on the physico-chemical properties of strontium
formate dihydrate crystals, (2012), Chem. Sci. Trans., (in press).
J. Angel Mary Greena, K. Karuppasamy, R. Antony, X. Sahaya Shajan and S. Kumaresan, Biocidal Action of Metal (Mg/Cu/Ni/Zn) Doped Strontium Formate
Dihydrate Crystal against Bacterial and Fungal Strains, (2012), Der Chemica Sinica, 3
(in press).
40.
J. Angel Mary Greena, K. Karuppasamy, R. Antony, X. Sahaya Shajan and S. Kumaresan, Spectral, DNA cleavage and antimicrobial activity studies of copper doped
strontium formate dihydrate crystals, (2012), Spectrochimica Acta A (Communicated).
41.
C. Shiju, D. Arish and S. Kumaresan, Novel water soluble Schiff base metal complexes: Synthesis, Characterization, antimicrobial, DNA cleavage, and Anticancer
Activity, (2012), Spectrochimica Acta A (Communicated).
42.
P. Palanisamy and S. Kumaresan, Synthesis, Characterization, Antimicrobial Activity and Antimycobacterial Activity of N, 1-Diphenyl-1,4-dihydrothiocromeno[4,3-
c]pyrazole-3-carboxamide Analogues, (2012), Journal of Bioorganic Chemistry
(Communicated).
43.
P. Palanisamy and S. Kumaresan, Analogues of N,1-Diphenyl-4,5-dihydro-1H- [1]benzothiepino[5,4-c]pyrazole-3-carboxamide N,1-Diphenyl-4,5-dihydro-1H- [1]benzothiepino[5,4-c]pyrazole-3-carboxamide-6,6-dioxide:Syntheses, Characterization,
Antimicrobial-, Antituberculosis-, and Antitumor Activity, Journal of Bioorganic
Chemistry and Medicinal Chemistry (Communicated).

Source: http://es.csirhrdg.res.in/pre_upload/DRP-958-Petchiammal-.pdf