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Science Chemistry

Kumar group

Kumar group photo

Group leader
Naresh Kumar

Naresh Kumar

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Research

Synthetic Organic and Medicinal Chemistry

The main focus of the research undertaken in my group is the discovery and development of novel bioactive molecules and their application in industrial and medical settings. Naturally produced chemicals are of fundamental importance in biological systems. Such chemicals are used to mediate interactions across all levels of biological hierarchy. Very often such diverse molecules are produced only in minute quantities. New or innovative organic syntheses not only provide access to sufficient quantities of these molecules but also their analogues. The access to various structurally-related analogues allows full assessment of their biological activity and mode of action, and offers opportunities to develop new therapeutic leads. The research is multi-disciplinary in nature and involves a combination of synthetic organic chemistry, molecular modelling and biological screening.

  • Quorum sensing inhibitors

    The emergence of multi-drug resistance in common human pathogens has highlighted the need to develop novel classes of antimicrobials for the treatment of human disease. A number of projects are available in this area focussing on a combination of organic synthesis, molecular modelling, and in vitro and in vivo antimicrobial screening. This project will develop novel antagonists of bacterial signalling pathways, which inhibit the regulatory quorum sensing communication pathways of bacteria, and will model the receptor-ligand interaction using the X-ray crystal structures of bacterial signal receptors e.g. Pseudomonas quinolone system (PQS).

    • Sabir S et al., (2021) Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa. Bioorganic & Medicinal Chemistry, 31:115967.
    • Almohaywi B et al., (2019) Dihydropyrrolones as bacterial quorum sensing inhibitors, Bioorg & Med Chem Lett, 29:1054-1059.
    • Nizalapur S et al., (2017) Synthesis and biological evaluation of novel acylic and cyclic glyoxamide based derivatives as bacterial quorum sensing and biofilm inhibitors, Organic & Biomolecular Chemistry, 15:5743-5755.
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    New scaffolds and hydrogels for antimicrobial discovery

    (in collaboration with Prof. David StC Black, Dr Rajesh Kuppusamy ʹڲƱ)

    The majority of conventional antibiotics used today share a common feature in that they act on specific molecular targets. Having very well-defined targets, these drugs act with a high degree of selectivity, minimizing unwanted side effects. However, a major limitation of antibiotics targeting a single receptor is the ease with which resistance can be developed. The central aim of this project is to design novel small molecular antimicrobial peptide (SMAMP) mimics based on glyoxylamides and anthranilamides, which disrupt the normal functioning of the membranes of the bacterial cell, and as a consequence allow the development of antimicrobial agents and gels with enhanced activity and the ability to bypass resistance mechanisms used by bacteria against other antibiotic types.

    • Yu TT et al., (2020) Design, synthesis and biological evaluation of biphenylglyoxamide-based small molecular antimicrobial peptide mimics as antibacterial agents, International Journal of Molecular Sciences 21:6789.
    • Kuppusamy R et al., (2018) Guanidine functionalized anthranilamides as effective antibacterials with biofilm disruption activity, Organic and Biomolecular Chemistry, 32:5871-5888.
    • Aldilla VR, Chen R, Martin AD, Marjo CE, Rich AM, Black DS, Thordarson P, Kumar N, (2020) Anthranilamide-based short peptides self-assembled hydrogels as antibacterial agents. Scientific reports, 10:770.
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    Inhibitors of Bacterial Transcription Initiation

    (in collaboration with Prof. Peter Lewis, University of Newcastle)

    The enzyme RNA polymerase (RNAP) that transcribes DNA into RNA is highly conserved across species. However, the factors that regulate the activity of RNAP are target-specific. Therefore, the unique interaction of sigma factors with RNAP in bacteria represents an ideal target for the development of small molecules that can specifically inhibit this interaction3. In this project new molecules that target these essential protein-protein interactions will be rationally designed and synthesized, and evaluated for their antimicrobial efficacy. These new small molecules would represent lead compounds for the development of new antibiotics.

    • Wenholz D et al., (2017) Small molecule inhibitors of bacterial transcription complex formation, Bioorg & Med Chem Lett, 27:4302-4308.
    • Thach O et al., (2016) From indole to pyrrole, furan, thiophene and pyridine: Search for novel small molecule inhibitors of bacterial transcription tnitiation complex formation, Bioorganic & Medicinal Chemistry, 24:1171-1182.
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  • Novel Heterocyclic Analogues of Isoflavones as Anticancer Agents

    (in collaboration with Dr Daniel Wenholz ʹڲƱ)

    The isoflavones are the largest and most widely studied class of phytoestrogens displaying potent and selective cytotoxicity against cancer cells, with low toxicity to healthy cells. During the past five years we have developed several new phenoxodiol conjugates with potent biological activities, and have also incorporated phenoxodiol in a cyclodextrin formulation, which shows increased aqueous solubility.
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    Furthermore we have covalently conjugated phenoxodiol to dextran to generate a new product with enhanced stability and efficacy. In addition, we have developed methodologies for the synthesis of novel analogues of fused flavonoid natural products, including dependensin, rottlerin and kamalachalcone A. The overall aim of the project is to synthesize novel heterocyclic analogues of isoflavones. The specific objectives of the proposal are to synthesize aza-isoflavone structural analogues and to evaluate their biological activity using in vitro assays to identify structure-activity relationships as a means of refining synthetic targets to ultimately develop lead candidates.

    • Yee EMH, Cirillo G, Brandl MB, Black DStC, Vittorio O, Kumar N. (2019) Synthesis of dextran-phenoxodiol and evaluation of its physical Stability and biological activity,Frontiers in Bioengineering and Biotechnology, 7:183.
    • Yee EMH, Hook JM, Bhadbhade MM, Vittorio O, Brandl MB, Black DStC, Kumar N. (2017) Preparation, characterization and in vitro biological evaluation of (1:2) phenoxodiol-β-cyclodextrin complex. Carbohydrate Polymers, 165:444-454.

    Targeting MYCN with New Scaffolds for Anticancer Discovery

    (in collaboration Dr Belamy Cheung and Prof Glenn Marshall CCIA, ʹڲƱ)

    Neuroblastoma (NB) is the most common extracranial solid tumour in early childhood, and it accounts for approximately 8% of all paediatric cancer and 15% of childhood cancer mortality. Approximately 20% of all NB cases experience MYCN oncogene amplification and overexpression, which is related to poor prognosis. Although this suggests a new therapeutic option for NB, developing molecules that directly target at MYCN protein has been challenging due to its structure with no apparent pocket for small molecule binding, its nuclear location and potential side effects in normal proliferating tissues. Among the pathways that control MYCN stability, ubiquitination is the most prominent mechanism. De-ubiquitination prevents ubiquitination, in which the degradation of MYCN is inhibited. Ubiquitin specific proteases (USPs) are de-ubiquitinating enzymes (DUBs) that play an essential role in the stability of MYCN by de-ubiquitination. Downregulation of USP5 leads to suppression of tumour suppressor protein p53, and inhibition of USP5 restores cell cycle check point control, leading to the induction of apoptosis. Therefore, developing novel inhibitors for USP5 could be a significant advancement for NB therapy. The overall aim of this project is to synthesize new scaffolds for inhibiting for USP5 and test theirin vitroԻin vivoefficacy.

    • Gadde S, Leung YC, Bhadbade M, Cheung BB, Black DS, Kumar N, (2020) Synthesis of a novel library of 1-substituted pyrido [1, 2-a] benzimidazoles. Australian Journal of Chemistry,73: 1208-1218.

    Compounds That Activate Glucose Oxidation

    (in collaboration with Dr Frances Byrne and A/Prof Kyle Hoehn, BABS, ʹڲƱ)

    Cancer is a major burden of disease, affecting the lives of tens of millions on a global scale.A hallmark feature of nearly all cancer cells is their altered metabolism of glucose compared to non-cancerous cells. Relative to most normal cells, cancer cells use a greater proportion of incoming glucose for non-oxidative purposes including the production of building blocks for cell division (lipid, DNA and protein), rather than oxidative pathways that produce carbon dioxide (CO2) in mitochondria. The goal of this proposal is to develop anticancer molecules that change cancer cell glucose metabolism to be more like that of non-cancerous cells. We have identified a small molecule that increases glucose oxidation and selectively kills cancer cells in vitro and in mice. The aim of this project is to generate new derivatives with enhanced activity and drug-like properties. The new compounds will be evaluated for anticancer activity in various cancer cell lines.

    • Byrne FL, Olzomer EM, Marriott GR, Quek LE, Katen A, Su, J, Kumar N, Hoehn KLet al. (2020) Phenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial oxidative stress. Redox Biol, 28:101374.
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  • (in collaboration with Prof David Black)

    Flavones and isoflavones are two structurally related large and diverse groups of natural compounds with broad spectra of biological activities including antioxidant, anticancer, antiviral and anti-inflammatory properties. They are recognized as “privileged” medicinal chemistry molecular frameworks because they are commonly found in biologically active compounds that show drug-like characteristics.Rottlerin is a flavonoid isolated from the fruits of a medicinal plant, \Malloutus philippensis. Our group has reported the successful synthesis of rottlerin via theacid-catalysed reaction of 5,7,8-trimethoxyflavene.A number of projects are available in this area focussing on the design and synthesis ofnew azaflavone ana