Drugs acting on central nervous system (CNS) targets as leads for non-CNS targets

Out-of-the-box approaches are currently needed to replenish the souring pipelines of pharmaceutical companies across the globe. Here a theme is presented – the use of central nervous system (CNS) drugs as leads for non-CNS targets. The approach is related to the use of existing drugs for new indications. Suitable chemical modifications of the CNS drugs abolish their CNS penetration. These novel analogs may then be screened for activity against non-CNS targets. Careful selection of the appropriate structural modifications remains the key to success

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

1215-1222A 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)

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).

Molecular insights into Coumarin analogues as antimicrobial agents: Recent developments in drug discovery

A major global health risk has been witnessed with the development of drug-resistant bacteria and multidrug-resistant pathogens linked to significant mortality. Coumarins are heterocyclic compounds belonging to the benzophenone class enriched in different plants. Coumarins and their derivatives have a wide range of biological activity, including antibacterial, anticoagulant, antioxidant, anti-inflammatory, antiviral, antitumour, and enzyme inhibitory effects. In the past few years, attempts have been reported towards the optimization, synthesis, and evaluation of novel coumarin analogues as antimicrobial agents. Several coumarin-based antibiotic hybrids have been developed, and the majority of them were reported to exhibit potential antibacterial effects. In the present work, studies reported from 2016 to 2020 about antimicrobial coumarin analogues are the focus. The diverse biological spectrum of coumarins can be attributed to their free radical scavenging abilities. In addition to various synthetic strategies developed, some of the structural features include a heterocyclic ring with electron-withdrawing/donating groups conjugated with the coumarin nucleus. The suggested structure−activity relationship (SAR) can provide insight into how coumarin hybrids can be rationally improved against multidrug-resistant bacteria. The present work demonstrates molecular insights for coumarin derivatives having antimicrobial properties from the recent past. The detailed SAR outcomes will benefit towards leading optimization during the discovery and development of novel antimicrobial therapeutics

Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure–activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines. Few title compounds exhibited cellular activity profile better than MPA itself. The observed differences in the overall biological profile could be attributed to improved structural and physicochemical properties of the analogues over MPA. This is the first report of the activity of MPA derivatives in glioblastoma, the most aggressive brain cancer

Newer human inosine 5′-monophosphate dehydrogenase 2 (<i>h</i>IMPDH2) inhibitors as potential anticancer agents

<p>Human inosine 5′-monophosphate dehydrogenase 2 (<i>h</i>IMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure–activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for <i>h</i>IMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines. Few title compounds exhibited cellular activity profile better than MPA itself. The observed differences in the overall biological profile could be attributed to improved structural and physicochemical properties of the analogues over MPA. This is the first report of the activity of MPA derivatives in glioblastoma, the most aggressive brain cancer.</p

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)