PHARMACOPHORE MODELLING FOR THE DISCOVERY OF SYSTEM XC- ANTIPORTER INHIBITORS

Cancer is one of the major disorders with increasing rates of morbidity and mortality. Recent drug discovery of anti cancer drug has identified several molecular targets and tried to achieve a goal of therapeutic effecative and safe molecule. Amongst these, system xc- antiporter is a novel promising target to control cancer progression. This antiporter is found to be over expressed in majority of cancer cells and functions by transporting amino acids, cystine and glutamate, in opposite directions. System xc- antiporter uptakes one molecule of cystine with the release of one molecule of glutamate in extracellular space. As already known cystine is precursor for the synthesis of glutathione, an in vivo antioxidant which is utilized by cancer cells to combat oxidative stress. At the other side the released glutamate (an excitatory neurotransmitter), when released in higher concentration, may over excite neurones (specifically and brain tumour) causing cell death to metastasise cancer cells. Therefore, through inhibition of system xc- antiporter, it is possible to kill cancer cells by disturbing their redox status along with through prevention of excitotoxcity by glutamate. In context to this, several researches have reported diverse molecules having system xc- antiporter inhibition potential. Amongst these molecules, erastin and its analogues are most potent system xc- antiporter inhibitors but it lacks preclinical data. Moreover, sulfasalazine, a FDA approved drug also showed good inhibition potential against this antiporter and therefore in our study we have attempted to construct pharmacophore model using this series to aid in the discovery of potent inhibitors with desirable safety. Results of this study exhibited successful development of pharmacophore model with phase survival score. Additionally, fit scores of sulfasalazine analogues were also in acceptable range. Hence, the developed pharmacophore model may be used for design of potent System xc- antiporter inhibitors

Synthesis, molecular docking and biological evaluation of new quinoline analogues as potent anti-breast cancer and antibacterial agents

A new class of quinoline analogues have been synthesized from isatin through two steps in good yields. They have been further evaluated for their anticancer activity against a breast cancer cell line (MDA-MB-231) and antibacterial activity against Gram-positive bacteria (Staphylococcus aureus 6538p and Bacillus subtilis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). All synthesized compounds have been confirmed by spectral characterization viz. FT-IR, MS, HPLC, 1H and 13C NMR. Among them, compound 4h exhibits promising anti-breast cancer activity whereas compounds 4d, 4f, 4h and 4j exhibit moderate antibacterial activity against all the tested organisms. Molecular docking analysis demonstrates the interaction of compound 4h with the active site amino acid of Human Carbonic Anhydrase I, Protein Kinase A and Kinesin Spindle Protein (KSP).

Azole compounds designed by molecular modelling show antifungal activity as predicted

372-381Rational approaches involving drug discovery technologies such as computational and combinatorial chemistry and high throughput screening have been useful tools to design and discover new drugs more efficiently. The interplay among structure-activity relationships, computer modelling, chemical synthesis and pharmacological testing can lead to better products for a particular therapeutic purpose. The work presented in this paper reports an example of successful application of computer-aided drug design method to find new azole antifungal agents. The designed compounds have been synthesized in the laboratory and tested for anti fungal activity against Candida albicans ATCC 24433 in vitro. Two compounds exhibit good activity in vitro, which can be optimized for better activity

Synthesis, Molecular Docking and Biological Evaluation of New Quinoline Analogues as Potent Anti-breast Cancer and Antibacterial Agents: Synthesis and Biological Evaluation of New Quinoline Analogues

A series of new class of quinoline analogues were synthesized from isatin through two steps in good yields. All compounds were further evaluated for their anticancer activity against triple-negative breast cancer cell line (MDA-MB-231) using MTT assay and antibacterial activity against Gram-positive bacteria (Staphylococcus aureus 6538p and Bacillus subtilis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) using agar well diffusion method. All synthesized compounds were confirmed by spectral characterization viz FT-IR, MS, 1H-NMR, and 13C-NMR. Results indicated that in vitro anticancer evaluation, IC50 values of all target compounds were in the range of 11.50-37.99 μM and compound 4h showed better promising anti-breast cancer activity among all synthesized derivatives. In vitro antibacterial evaluation, compounds 4d, 4f, 4h, and 4j showed moderate antibacterial activity among all derivatives. Molecular docking analysis demonstrated good interaction of compound 4h with the active site residue of Human Carbonic Anhydrase I, Protein Kinase A, and Kinesin Spindle Protein (KSP)

Inhibition of carbonic anhydrase isoforms I, II, IX and XII with Schiff’s bases incorporating iminoureido moieties

<div><p></p><p>A series of new Schiff’s bases was obtained from the sulfanilamide semicarbazone (4-aminosulfonylphenyl semicarbazide) and aromatic/heterocyclic aldehydes. The new compounds were designed to incorporate moieties known to induce effective inhibitory activity against carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in crucial physiologic or pathologic processes such as the cytosolic CA I and II or the transmembrane, tumor-associated CA IX and XII: the compounds were medium potency – weak CA I inhibitors, highly effective, low nanomolar CA II inhibitors, but few of them inhibited effectively CA IX and XII. This may probably due to the long spacer between the sulfamoylphenyl and imine fragments of the molecules, which probably induces a highly flexible conformation of the inhibitor bound to the active site of the enzyme, with destabilizing effects for the adduct. The detailed structure activity relationship for this class of inhibitors is discussed.</p></div

Human Milk Oligosaccharides as Potential Antibiofilm Agents: A Review

Surface-associated bacterial communities called biofilms are ubiquitous in nature. Biofilms are detrimental in medical settings due to their high tolerance to antibiotics and may alter the final pathophysiological outcome of many healthcare-related infections. Several innovative prophylactic and therapeutic strategies targeting specific mechanisms and/or pathways have been discovered and exploited in the clinic. One such emerging and original approach to dealing with biofilms is the use of human milk oligosaccharides (HMOs), which are the third most abundant solid component in human milk after lactose and lipids. HMOs are safe to consume (GRAS status) and act as prebiotics by inducing the growth and colonization of gut microbiota, in addition to strengthening the intestinal epithelial barrier, thereby protecting from pathogens. Moreover, HMOs can disrupt biofilm formation and inhibit the growth of specific microbes. In the present review, we summarize the potential of HMOs as antibacterial and antibiofilm agents and, hence, propose further investigations on using HMOs for new-age therapeutic interventions