Zubair Shanib Bhat

Inflammation in Ischemic Stroke: Mechanisms, Consequences and Possible Drug Targets

Ischemic stroke is caused when blood flow to the brain is hampered, leading to instant deficiency of nutrients and oxygen required for normal brain functioning. Reperfusion can alleviate damage from stroke if performed immediately after the onset of ischemia however the efficacy of reperfusion is tempered by secondary injury mechanisms. This multifarious sequence of events leads to the commencement of deleterious cycles of inflammation, oxidant stress and apoptosis that finally culminate in delayed death of neuronal cells even when the brain is effectively reperfused. Wealth of data from clinical as well as experimental studies points to a prominent role of inflammation in secondary injury. In this review we will discuss, in detail, the cellular and molecular mediators of inflammation and their possible therapeutic targets in both experimental and clinical forms of stroke.

α-pyrones: Small molecules with versatile structural diversity reflected in multiple pharmacological activities-an update

The investigations in the chemistry and biology of α-pyrone (2-pyrone) are of vital importance as they constitute an essential pharmacophore in many naturally occurring and biologically active synthetic agents. They are a promising class of biorenewable platform chemicals that provide access to an array of chemical products and intermediates. Literature survey reveals that a simple change in the substitution pattern on the 2-pyrone ring system often leads to diverse biological activities. In this review, we present a brief overview of 2-pyrone pharmacophore followed by highlighting their pharmacological properties and potential applicability till date. Particular attention is focused on the distinctive chemotherapeutic activities of 2-pyrones as anti-HIV, anti-TB and anti-cancer agents followed by their potential role against neurodegeneration, hypercholesterolemia, microbial infections, chronic obstructive lung disease, inflammation, antinociception and immunomodulation. Since 2005, when 2-pyrones came in limelight, their detailed pharmacological activities have been well documented. This review has mainly been prepared on the basis of original reports published in recent two decades with an aim to attract the attention of researchers towards this versatile scaffold for future endeavors that may lead to the development of potential drug candidates against above diseases.

Synthesis and in vitro evaluation of 2-(((2-ether)amino)methylene)-dimedone derivatives as potential antimicrobial agents

The study was designed with an aim to synthesize a series of 2-(((2-ether)amino)methylene)-dimedone derivatives and evaluate the synthesized compounds for antimicrobial activity. Compound library was synthesized by reaction with alkyl, alkenyl, alkynyl and alicyclic bromo-compounds. Characterization of the synthesized compounds was performed by 1H NMR, 13C NMR and mass spectral techniques. The compounds were evaluated for their antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus subtilis, Clostridium sporogenes) and Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli). The activity of these compounds was also evaluated against fungi (Aspergillus fumigatus, Penicillium chrysogenum, Fusarium oxysporum, Candida albicans) and molds (A. niger and A. oryzae). Broth microdilution method and CLSI guidelines with minor modification were used for the determination of anti-bacterial and antifungal activity, respectively. Although four compounds (4i, 4j, 4k and 4l) showed good antibacterial activity but compound 4k was found to be most active chemotype in the series. Compound 4k was found to be active against S. aureus, B. cereus and B. subtilis bacterial strains at one dilution lower compared to the control ciprofloxacin. Antibacterial activity of compound 4k was comparable to ciprofloxacin against S. pyogenes and M. luteus. The compound 4d, 4e and 4s showed good antifungal and antimold activity compared to other chemotypes. However, in comparison to fluconazole both the compounds showed lower activity. The results merit the antimicrobial promise of the 2-(((2-ether)amino)methylene)-dimedone analogs.

Cell wall: A versatile fountain of drug targets in Mycobacterium tuberculosis

Tuberculosis is the leading infectious disease responsible for an estimated one and a half million human deaths each year around the globe. HIV-TB coinfection and rapid increase in the emergence of drug resistant forms of TB is a dangerous scenario. This underlines the urgent need for new drugs with novel mechanism of action. A plethora of literature exist that highlight the importance of enzymes involved in the biosynthesis of mycobacterial cell wall responsible for its survival, growth, permeability, virulence and resistance to antibiotics. Therefore, assembly of cell wall components is an attractive target for the development of chemotherapeutics against Mycobacterium tuberculosis. The aim of this review is to highlight novel sets of enzyme inhibitors that disrupt its cell wall biosynthetic pathway. These include the currently approved first and second line drugs, candidates in clinical trials and current structure activity guided endeavors of scientific community to identify new potent inhibitors with least cytotoxicity and better efficacy against emergence of drug resistance till date.

Antituberculotic activity of actinobacteria isolated from the rare habitats

A distinctive screening procedure resulted in the isolation and identification of antituberculotic actinobacteria. In this course, a total of 125 actinobacteria were isolated from various soil samples from untapped areas in Northwestern Himalayas, India. The antibacterial screening showed that 26 isolates inhibited the growth of at least one of the tested bacterial pathogens including Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis (ATCC 12228), Bacillus subtilis (ATCC 11774), Micrococcus luteus (ATCC 10240), Escherichia coli (10536), Pseudomonas aeruginosa (ATCC 10145) and Klebsiella pneumonia (ATCC BAA‐2146). The production media was optimized for the active strains by estimation of their extract value by the quantification of the ethyl acetate extract. The screening of fermentation products from the selected 26 bioactive isolates revealed that 10 strains have metabolites antagonistic against the standard H37Rv strain of Mycobacterium tuberculosis. The characterization by 16S rRNA gene sequencing and phylogenetic analysis demonstrated the diverse nature of these antituberculosis strains. The secondary metabolites of potent, rare strain, Lentzea violacea AS08 exhibited promising antituberculosis activity with minimal inhibitory concentration (MIC) of 3·9 μg ml−1. The metabolites identified by gas chromatography–mass spectrometry (GC–MS) included, Phenol, 2,5‐bis (1, 1‐dimethylethyl), n‐Hexadecanoic acid, Hexadecanoic acid methyl‐ester, Hexadecanoic acid ethyl‐ester and, 9,12‐Octadecadienoyl chloride(Z,Z) are biologically significant molecules.

In vitro antimycobacterial activity of 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione: a new chemical entity against Mycobacterium tuberculosis

This study reports on the in vitro antituberculosis potential of 2-(((2-hydroxyphenyl) amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (PAMCHD) against Mycobacterium tuberculosis H37Rv. PAMCHD has been proven to be a tuberculostatic as well as a tuberculocidal agent by agar and broth dilution methods with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values equivalent to some standard antituberculosis drugs (ATDs). The dynamics of M. tuberculosis killing revealed the time- as well as concentration-dependent antituberculosis activity of PAMCHD and it sterilized M. tuberculosis culture at or above 10.0 µg/mL. PAMCHD acts either synergistically or additively with ATDs. Isoniazid (INH) and PAMCHD post-antibiotic effects increased with concentration from 16.18 ± 13.30 and 31.64 ± 13.30 to 127.9 ± 27.60 and 138.71 ± 16.42 h, respectively, from 1 × MIC to 8 × MIC; no significant difference was observed between INH and PAMCHD post-antibiotic effects. M. tuberculosis mutation frequency against PAMCHD is lower than that of INH. Mutant prevention concentration (MPC) of INH, rifampin (RIF) and PAMCHD were observed to be 40, 160 and 160 µg/mL, respectively, and their MPC/MIC values were 128, 2051 and 64, respectively; this lowest MPC/MIC highlights the advantage of PAMCHD over RIF and INH.

Drug targets exploited in Mycobacterium tuberculosis: Pitfalls and promises on the horizon

Tuberculosis is an ever evolving infectious disease that still claims about 1.8 million human lives each year around the globe. Although modern chemotherapy has played a pivotal role in combating TB, the increasing emergence of drug-resistant TB aligned with HIV pandemic threaten its control. This highlights both the need to understand how our current drugs work and the need to develop new and more effective drugs. TB drug discovery is revisiting the clinically validated drug targets in Mycobacterium tuberculosis using whole-cell phenotypic assays in search of better therapeutic scaffolds. Herein, we review the promises of current TB drug regimens, major pitfalls faced, key drug targets exploited so far in M. tuberculosis along with the status of newly discovered drugs against drug resistant forms of TB. New antituberculosis regimens that use lesser number of drugs, require shorter duration of treatment, are equally effective against susceptible and resistant forms of disease, have acceptable toxicity profiles and behave friendly with anti-HIV regimens remains top most priority in TB drug discovery.

α-pyrones and their hydroxylated analogs as promising scaffolds against Mycobacterium tuberculosis

Tuberculosis ranks as the leading cause of global human mortality from a single infectious agent. To address the uprising issues of drug resistance, intense research efforts have been directed towards drug discovery. However, it is a long and economically challenging process that is often associated with high failure rates. Therefore, it seems prudent to take forward the core scaffolds that have already acclaimed clinical relevance. In this direction, hydroxylated α-pyrone scaffold has received US FDA approval for human use against HIV. Interestingly, literature review reveals the potential applicability of α-pyrones in TB drug discovery. On one hand, α-pyrones play a vital role in the cell wall of Mycobacterium tuberculosis and on the other hand natural α-pyrones display appreciable anti-TB activity. This review aims to rekindle the interest of researchers toward α-pyrone as a new anti-TB drug that may possibly tackle drug resistance and open a dual frontier in TB and HIV drug discovery.

Comparative analysis of bioactive N-alkylamides produced by tissue culture raised versus field plantlets of Spilanthes ciliata using LC-Q-TOF (HRMS)

Spilanthes ciliata (S. ciliata) is a perennial herb of global importance owing to its luscious source of bioactive fatty acid derived amides known as N-alkylamides. It finds application in skin creams, mouth gels and toothpastes. Despite multifaceted applications, a major limitation associated for its commercial application is the scarcity of contamination free plant source, fluctuations in active metabolites due to variation in extraction procedures, and lack of rapid qualitative method for alkylamide profiling. In the current work, attempts were made to 1) optimize conditions for mass propagation of contamination free plants of S. ciliata by tissue culture using leaf discs as explants, 2) establish an optimum extraction ratio of plant/solvent (w/v) for maximum elution of alkylamides and 3) develop a rapid method for qualitative estimation of alkylamide from in vitro raised plants in comparison with that of the field grown counterpart by using LC-Q-TOF (HRMS). To the best of our knowledge, this is the first qualitative report on alkylamide profile of micropropagated whole plant of Spilanthes. The correlation pattern reported in this study may form the basis for using tissue culture raised plantlets of S. ciliata as potential source of bioactive alkylamides on industrial scale.