Browsing by Author "Satheeshkumar Sellamuthu"

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Design, synthesis and biological evaluation of carbazole derivatives as antitubercular and antibacterial agents
(Bentham Science Publishers B.V., 2019) Satheeshkumar Sellamuthu; Mohammad F. Bhat; Ashok Kumar; Gopal Nath; Sushil K. Singh
Background: The neuroleptic chlorpromazine has been reported for antitubercular activity but the associated antipsychotic activity restricted its clinical presentation. Objectives: Novel derivatives of carbazole having structural similarity with chlorpromazine were designed, in an attempt to reduce the associated side effects, while retaining the antitubercular activity. Materials and Methods: The designed molecules were synthesized and screened for antitubercular and antibacterial activities. The blood-brain barrier (BBB) permeability and mammalian cell (VERO) cytotoxicity (CC50) were examined to determine the safety of compounds. Results: Among the developed compounds, 14c, 15c, 16c and 17c were found to be promising against Mtb H37Rv at MIC of 1.56 μg/ml. They were also effective against S. aureus and E. coli at MIC of 0.98 and 7.81 μg/ml, respectively. The BBB permeability of the compounds was found to be less than chlorpromazine. Therefore, the developed compounds are expected to have diminished antipsychotic effect. The compounds were further marked safe against mammalian VERO cells at CC 50 > 90 μg/ml. Conclusion: The profound antitubercular activity with a concomitant reduction in BBB permeability of carbazole derivatives can pave new vista in the discovery of antitubercular drugs. © 2019 Bentham Science Publishers.
Design, synthesis and biological profiling of novel phenothiazine derivatives as potent antitubercular agents
(Bentham Science Publishers B.V., 2019) Satheeshkumar Sellamuthu; Ashok Kumar; Gopal Nath; Sushil Kumar Singh
Background: Neuroleptic phenothiazines have been reported for antitubercular activity, but the unwanted side effect (antipsychotic activity) restricted their use as antitubercular drugs. Objective: The study aimed to carry out development of phenothiazine based antitubercular agents by modifying/removing the chemical group(s)/ linker(s) of chlorpromazine essential for exerting an antipsychotic effect. Methods: The designed molecules were filtered with a cut-off of docking score < 2.0 Kcal/mol against dopamine receptors, so that their binding with the receptor would be reduced to produce no/ less antipsychotic effect. The molecules were then synthesized and screened against M. tuberculosis H37Rv. They were further screened against a gram-positive (S. aureus) and a gram-negative (E. coli) bacterial strains to evaluate the spectrum of activity. The ability of the compounds to cross the blood-brain barrier (BBB) was also analyzed. The compounds were further examined for cytotoxicity (CC 50 ) against mammalian VERO cells. Results: Compounds 14p, 15p and 16p were found to be the most effective against all the strains viz. M. tuberculosis H37Rv, S. aureus and E. coli with MIC of 1.56µg/ml, 0.98µg/ml and 3.91µg/ml, respectively. Further, BBB permeability was found to be diminished in comparison to chlorpromazine, which would ultimately reduce the unwanted antipsychotic activity. They were also found to be free from toxicity against VERO cells. Conclusion: The designed strategy, to enhance the antitubercular activity with concomitant reduction of dopamine receptor binding and BBB permeability was proved to be fruitful. © 2019 Bentham Science Publishers.
Design, synthesis and mode of action of some new 2-(4'-aminophenyl) benzothiazole derivatives as potent antimicrobial agents
(Bentham Science Publishers B.V., 2016) Meenakshi Singh; Sudhir Kumar Singh; Mayank Gangwar; Satheeshkumar Sellamuthu; Gopal Nath; Sushil K. Singh
Background: The rapid evolution of antibiotic resistance poses a serious threat to public health. The development of heterocyclic benzothiazole derivatives, as efficient and potential agents, has been the focus of antibacterial drug discovery. Objective: Present study attempts to evaluate the antibacterial activity and mechanism of action of novel 2-(4'- aminophenyl) benzothiazole derivatives. Methods: Antibacterial activity of novel benzothiazole derivatives was evaluated by agar disc diffusion method against a panel of susceptible Gram-positive and Gram-negative strains. The mechanism of action was explored by bactericidal kinetics, membrane depolarization, fluorescent assisted cell cytometry and DNA cleavage studies. Results: Our findings revealed that compounds A07a and A07b turned out to be the most potent analogues having minimum inhibitory concentration values in the range of 3.91-31.2 g/ml against Staphylococcus aureus, Salmonella typhi, Pseudomonas aeruginosa and Escherichia coli. The new benzothiazole derivatives displayed different modes of action as elucidated by the studies on intact bacterial cells and plasmid DNA. The structure activity relationship studies showed prominent activity of compound A07a containing oxime moiety on carbonyl carbon along with less bulky electron releasing and lipophillic group (methoxy and chloro) in phenyl ring at C2 position of 2-(4'-aminophenyl) benzothiazole ring system. Conclusion: The potent antibacterial activity of compounds (A07a and A07b) was mediated by membrane perturbing and intracellular mode of actions. These results further validate the use of these derivatives in the treatment of microbial diseases and provide scope for further research. © 2016 Bentham Science Publishers.
Gelatin grafted poly(D,L-lactide) as an inhibitor of protein aggregation: An in vitro case study
(John Wiley and Sons Inc, 2020) Chelladurai Karthikeyan Balavigneswaran; Gaurav Kumar; Chandrasekaran Vignesh Kumar; Satheeshkumar Sellamuthu; Uvanesh Kasiviswanathan; Biswajit Ray; Vignesh Muthuvijayan; Sanjeev Kumar Mahto; Nira Misra
Amyloids are a group of proteins that are capable of forming aggregated amyloid fibrils, which is responsible for many neurodegenerative diseases including Alzheimer's disease (AD). In our previous study, synthesis and characterization of star-shaped poly(D,L-lactide)-b-gelatin (ss-pLG) have been reported. In the present work, we have extended our work to study ss-pLG against protein aggregation. To the best of our knowledge, this is the first report on the inhibition of amyloid fibrillation by protein grafted poly(D,L-lactide). Bovine serum albumin (BSA) was chosen as the model protein, which readily forms fibril under high temperature. We found that ss-pLG efficiently suppressed the fibril formation of BSA compared with gelatin (Gel), which was supported by Thioflavin T assay, circular dichroism (CD) spectroscopy and atomic force microscopy (AFM). In addition, ss-pLG significantly curtailed amyloid-induced hemolysis. We also found that incubation of ss-pLG with neuroblastoma cells (MC65) protected the cells from fibril-induced toxicity. The rescuing efficiency of ss-pLG was better than Gel, which could be attributed to the reduced lamella thickness in branched ss-pLG. These results suggest the significance of gelatin grafting, which probably allows gelatin to interact with the key residues of the amyloidogenic core of BSA effectively. © 2020 Wiley Periodicals LLC
Preliminary studies on ligand-based design and evaluation of new mycobacterial ATP synthase inhibitors
(Bentham Science Publishers B.V., 2018) Satheeshkumar Sellamuthu; Amer H. Asseri; Hojjat Ghasemi Goojani; Gopal Nath; Sushil K. Singh
Background: Tuberculosis is a threat to humankind due to the development of resistance against the existing drugs, so new drugs are an absolute necessity. Neuroleptic phenothiazines were reported for antitubercular activity, but the associated antipsychotic effect restricted their antitubercular use. Objective: Novel mycobacterial ATP synthase inhibitors having structural similarity with phenothiazines were designed in an attempt to develop potent antitubercular agents with no or less side effects. Methods: The designed molecules were synthesized and screened against Mycobacterium tuberculosis H37Rv (Mtb). The compounds with strongest growth inhibition of whole Mtb (S3, S4, S9, S10, and S16) were screened for ATP synthesis inhibition using inverted membrane vesicles from Mycobacterium smegmatis, and were also screened for blood-brain barrier (BBB) permeability and mammalian cell cytotoxicity to assess the possible side effects. Results: Among all the compounds, S9 and S10 were found to be the most active (6.25 µg/mL) against Mtb and were comparable to chlorpromazine (12.5 µg/mL). Moreover, the compounds inhibited ATP synthesis at IC50 of 14 and 10.4 µM, respectively. A better correlation between MIC and IC50 observed, indicated that the compounds acted through mycobacterial ATP synthase inhibition. The blood-brain barrier (BBB) crossing ability of the compounds (S9, S10) was found to be less, indicating diminished CNS side effects. The compounds (S3, S4, S9, S10, and S16) were also marked safe against mammalian VERO cells, as CC50 was > 102 µg/mL. Conclusion: The enhanced antitubercular activity with reduced BBB permeability exhibited by the compounds has good prospect to develop them as antitubercular drugs. © 2018 Bentham Science Publishers.