Cationic fullerene quinazolinone conjugates as Tuberculosis HGPRT Inhibitors

Synthesis and biological evaluation of cationic fullerene quinazolinone conjugates and their binding mode with modeled Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase enzyme.

Patel MB, Kumar SP, Valand NN, Jasrai YT, Menon SK.

Department of Chemistry, University School of Sciences, Gujarat University, Ahmedabad, Gujarat, 380009, India. Department of Bioinformatics, Applied Botany Centre, University School of Sciences, Gujarat University, Ahmedabad, Gujarat, 380009, India.

The present work reports a series of novel cationic fullerene derivatives bearing a substituted-quinazolinone moiety as a side arm. Fullerene-quinazolinone conjugates synthesized using the 1,3-dipolar cycloaddition reaction of C60 with azomethine ylides generated from the corresponding Schiff bases of substituted quinazolinone were characterized by elemental analysis, FT-IR, 1H NMR, 13C NMR and ESI-MS and screened for their antibacterial activity against Mycobacterium tuberculosis (H 37 Rv strain). All the compounds exhibited significant activity with the most effective having MIC in the range of 1.562-3.125 μg/mL. Compound 9f exhibited good biological activity compared to standard drugs. We developed a computational strategy based on the modeled M. tuberculosis hypoxanthine-guanine phosphoribosyltransferase (HGPRT) using homology modeling techniques and studied its binding pattern with synthesized fullerene derivatives. We then explored the surface geometry of the protein to place the cage adjacent to the active site while optimizing its quinazolinone side arm to establish H bonding with active site residues.

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http://link.springer.com/article/10.1007%2Fs00894-013-1820-1

Artemisinin Molecular Target

Structural Insights into the Theoretical Model of Plasmodium falciparum NADH Dehydrogenase and its Interaction with Artemisinin and Derivatives: Towards Global Health Therapeutics.

Kumar SP, Jasrai YT, Pandya HA, George LB, Patel SK.

Department of Bioinformatics, Applied Botany Centre, University School of Sciences , Gujarat University, Ahmedabad, India .

Abstract

It is a continuing quest to uncover the principal molecular targets of malarial parasites to understand the antimalarial activity and mechanism of action of artemisinin, a potent antimalarial. A series of parasite proteins are experimentally validated as potential targets, such as translationally controlled tumor protein (TCTP) and sarco/endoplasmic reticulum membrane calcium ATP-ase (SERCA). The present study addressed the development of a theoretical model of Plasmodium falciparum NADH dehydrogenase with inference from artemisinin in vivo inhibitory activity. We report here the predicted binding modes of artemisinin and its derivatives. The modeled protein resembled the structural architecture of flavoproteins and oxidoreductases, consisting of two Rossmann folds and dedicated binding sites for its cofactors. Docked poses of the ligand dataset revealed its interactions at or near the si face, indicating being activated. This may aid in generation of reactive oxygen species, thereby disrupting the membrane potential of parasite mitochondria and leading to the clearance from the blood. These observations open up new strategies for development of novel therapeutics, or improvement of existing pharmacotherapies against malaria, a major burden for global health.

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http://online.liebertpub.com/doi/abs/10.1089/omi.2012.0129

Novel cationic fullerene derivatized s-triazine scaffolds

Novel cationic fullerene derivatized s-triazine scaffolds as photoinduced DNA cleavage agents: design, synthesis, biological evaluation and computational investigation

Manishkumar B. Patel,^a   Uma Harikrishnan,^a   Nikunj N. Valand,^a  Deval S. Mehta,^c   Kuldeep V. Joshi,^a  Sivakumar Prasanth Kumar,^b   Kishor H. Chikhalia,^a  Linz Buoy George,^c   Yogesh T. Jasrai^b and   Shobhana K. Menon*^a 

a. Department of Chemistry, University School of Sciences, Gujarat University, Navrangpura, India 
b. Department of Bioinformatics, Applied Botany Centre (ABC), University School of Sciences, Gujarat University, Navrangpura, India

c. Department of Zoology and Biomedical Technology, University School of Sciences, Gujarat University, Navrangpura, India

A series of novel cationic fullerene (C₆₀) derivatives, bearing substituted s-triazine moiety as a side arm, synthesized by using the 1,3 dipolar cycloaddition reaction of C₆₀ with azomethine ylides generated from the corresponding Schiff bases of substituted s-triazine is reported. All the synthesized compounds were characterized by elemental analysis, FT-IR, ¹H NMR, ¹³C NMR and ESI-MS. The compounds 7a, 7d, 7e and 7f cleaved the supercoiled pBR322 DNA into nicked form efficiently upon visible light irradiation in the presence of NADH. The photoinduced superoxide radical and hydroxyl radical generated may act as molecular species causing the DNA scission. Further, the interaction of synthesized molecules with pBR322 plasmid DNA was investigated using computational approaches.

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http://pubs.rsc.org/en/content/articlelanding/2013/ra/c3ra40950c