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

Cosmic ray produced Mg<SUP>28</SUP>, Si<SUP>31</SUP>, S<SUP>38</SUP>, C<SUP>l38</SUP>, Cl<SUP>34m</SUP> and other short-lived radioisotopes in wet precipitation

The concentrations of seven radioisotopes, expected to be produced in the troposphere by interactions of secondary cosmic rays with atmospheric nuclei, have been measured in "fresh" rain collections. The half-lives of these isotopes range from about half an hour to a day. The procedures developed for rapid, specific and sensitive analyses of these nuclides are discussed. Detection of two of the isotopes studied, Cl39 (half-life: 55 mins.) and Na24 (15 hrs.), has been reported earlier by Winsberg and Rodel respectively. Amongst the remaining nuclides, two: S38 (2.9 hrs.) and Cl38 (37.3 mins.) were independently and almost simultaneously detected by us and Perkins and his collaborators. Three other isotopes, Cl34m (32 mins.), Si31 (2.6 hrs.) and Mg28 (21.2 hrs.), detected in the present work have not yet been reported elsewhere. The nature of cosmic ray secondary particles responsible for the production of these short-lived radionuclides in the troposphere is discussed. Isotope production is found to vary strongly with altitude in the troposphere; it increases by a factor of two every 1.5-2 km depending on the radioisotope under question. This fact combined with the availability of several isotopes of half-lives ranging from about half an hour to a day leads to the possibility of using them as tracers for studying short-term tropospheric processes, e.g. those occurring prior to and during condensation in a precipitating cloud. The implications of the present measurements are discussed

Genetic diversity and relationship among three goat breed of Maharashtra state of India

Genetic diversity and relationship among in the three goat breed of Maharashtra, India namely Berari, Osmanabadi and Sangamneri were evaluated based on 25 microsatellite markers. A total of 567 alleles were observed among 129 assayed animals across the three breeds. The most diverse breed was Sangamneri followed by Berari and the least diverse breed was Osmanabadi in terms of number of allele. The overall mean of gene diversity across the studied loci for the Berari, Osmanabadi and Sangamneri breeds were 0.906±0.006, 0.870±0.017 and 0.901±0.010, respectively. The overall Fis value (0.161) was higher and significantly different from zero indicating departure from random mating and suggested that some of the studied loci were homozygous in the populations. The lower level of genetic differentiation (Fst) among the three breeds (3.9%) under study implied that 96.1% of the total genetic variation corresponded to differences among individuals within breed. The genetic distance tended to be the least (0.4032) between Berari and Sangamneri, moderate (0.4834) between Sangamneri and Osmanabadi and the widest (0.6319) between Berari and Osmanabadi. Lower level of genetic differentiation among the three breeds showed intermixing of the populations as breeding tract of three bred overlap hence, this may pose a danger to the purity of the breed in the long run

An outbreak of methicillin-resistant Staphylococcus aureus (MRSA) infection in dermatology indoor patients

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. Indiscriminate and increased use of systemic antibiotics has led to the emergence of MRSA. Infected or colonized ward patients are the main reservoir of infection. Once colonized, the risk of subsequent local and systemic infections is high, especially in the elderly, and in debilitated and immunosuppressed patients. Methods: We report an outbreak of MRSA in the dermatology ward of a tertiary care hospital and describe measures taken to control it. Results: Ten patients were found to be MRSA positive over a span of three months while screening swabs from wet lesions in indoor patients. On the basis of risk assessment, they were treated with appropriate systemic and topical therapy. One patient died while the remaining nine patients showed a good response to therapy. All the MRSA isolates were found to be sensitive to vancomycin, teicoplanin and linezolid. Conclusion: This is the first case report of MRSA infection in dermatology indoor patients in India

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