Recently, ATP synthase inhibitor Bedaquiline was approved for the treatment of multi-drug resistant tuberculosis emphasizing the importance of oxidative phosphorylation for the survival of mycobacteria. ATP synthesis is primarily dependent on the generation of proton motive force through the electron transport chain in mycobacteria. The mycobacterial electron transport chain utilizes two terminal oxidases for the reduction of oxygen, namely the bc1-aa3 supercomplex and the cytochrome bd oxidase. The bc1-aa3 supercomplex is an energy-efficient terminal oxidase that pumps out four vectoral protons, besides consuming four scalar protons during the transfer of electrons from menaquinone to molecular oxygen. In the past few years, several inhibitors of bc1-aa3 supercomplex have been developed, out of which, Q203 belonging to the class of imidazopyridine, has moved to clinical trials. Recently, the crystal structure of the mycobacterial cytochrome bc1-aa3 supercomplex was solved, providing details of the route of transfer of electrons from menaquinone to molecular oxygen. Besides providing insights into the molecular functioning, crystal structure is aiding in the targeted drug development. On the other hand, the second respiratory terminal oxidase of the mycobacterial respiratory chain, cytochrome bd oxidase, does not pump out the vectoral protons and is energetically less efficient. However, it can detoxify the reactive oxygen species and facilitate mycobacterial survival during a multitude of stresses. Quinolone derivatives (CK-2-63) and quinone derivative (Aurachin D) inhibit cytochrome bd oxidase. Notably, ablation of both the two terminal oxidases simultaneously through genetic methods or pharmacological inhibition leads to the rapid death of the mycobacterial cells. Thus, terminal oxidases have emerged as important drug targets. In this review, we have described the current understanding of the functioning of these two oxidases, their physiological relevance to mycobacteria, and their inhibitors. Besides these, we also describe the alternative terminal complexes that are used by mycobacteria to maintain energized membrane during hypoxia and anaerobic conditions.
Abstract A base‐mediated one‐pot, two‐step, four‐component reaction has been developed to synthesize imidazole‐4(2 H )‐ones, utilizing commercially available amino acid esters, aldehydes, alkynes, and amino alcohols. Control experiments and isolation of the intermediate revealed the mechanistic details. This four‐component reaction proceeds via imine formation, followed by the nucleophilic addition of alkyne to form a propargylamine precursor. Subsequently, the propargylamine precursor under undergoes base‐mediated conversion into 1‐azadiene, followed by in situ ketene formation to generate (allylideneamino)prop‐1‐en‐1‐one. The nucleophilic addition of amino alcohol and subsequent intramolecular cyclization provides imidazole‐4 (2 H )‐ones exclusively.
Benzothiazine 1,1-dioxide (BTDO) is a privileged chemical motif, and its metal-free domino access is in high demand. Current BTDO production methods require costly metal catalysts or harsh reaction conditions. A facile domino approach to BTDO via a water-gas shift reaction (WGSR) employing sodium 2-nitrobenzenesulfinates and α-bromo ketones is presented. This strategy is cost-effective and environmentally beneficial. The optimized reaction conditions demonstrated remarkable chemical tolerance to a wide range of electrically and sterically varied substituents on both coupling partners.
A Rh(III)-catalyzed [4 + 1] cyclization of 2-arylbenzimidazoles with alkynoates through C-H activation/ortho-alkenylation/intramolecular annulation cascade to obtain benzimidazole-fused isoindoles is reported. The reaction of the Rh catalyst and internal alkyne ester provides benzo[4,5]imidazo[2,1-a]isoindole acetate exclusively. Conversely, internal alkyne amide participates in the annulation process in the presence of a Ru catalyst to provide benzo[4,5]imidazo[2,1-a]isoindole acetamide. The alkyne acts as a C1 synthon and undergoes [4 + 1] cyclization rather than traditional [4 + 2] annulation.
Abstract A one‐pot, three‐component, base‐mediated [3+2] cycloaddition reaction to synthesize 1 H ‐pyrrol‐3(2 H )‐ones from readily available amino acid esters, aldehydes, and terminal alkynes was reported. Isolation of the intermediate and the detailed mechanistic study revealed the course of the reaction. This multi‐component reaction proceeds via imine formation followed by the nucleophilic addition of alkyne to form a propargylamine precursor. Base‐mediated conversion of propargylamine precursor into 1‐azadiene followed by in situ ketene formation leading to [3+2] cycloaddition that ultimately produces unusual 1 H ‐pyrrol‐3(2 H )‐ones.
Abstract Isodesmosine is 1,2,3,5‐tetrasubstituted pyridinium‐based amino acid substituted with four lysine derivatives found in elastin which is the main component of elastic fiber. Elastin plays a vital role in providing stretchy properties to tissues and body organs. Isodesmsoine is a proven to be useful biomarker for elastin degradation during the progressing stage of chronic obstructive pulmonary disease (COPD) and related diseases. The present work reported an efficient and gram‐scale approach for the synthesis of Isodesmosine, starting from readily available Boc‐Asp‐O t Bu using mild reaction conditions.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) is the causative agent of Corona Virus Disease 2019 (COVID-19). Lower production of type I and III interferons and higher levels of inflammatory mediators upon SARS-CoV2 infection contribute to COVID-19 pathogenesis. Optimal interferon production and controlled inflammation are essential to limit COVID-19 pathogenesis. However, the aggravated inflammatory response observed in COVID-19 patients causes severe damage to the host and frequently advances to acute respiratory distress syndrome (ARDS). Toll-like receptor 7 and 8 (TLR7/8) signaling pathways play a central role in regulating induction of interferons (IFNs) and inflammatory mediators in dendritic cells. Controlled inflammation is possible through regulation of TLR mediated response without influencing interferon production to reduce COVID-19 pathogenesis. This review focuses on inflammatory mediators that contribute to pathogenic effects and the role of TLR pathways in the induction of interferon and inflammatory mediators and their contribution to COVID-19 pathogenesis. We conclude that potential TLR7/8 agonists inducing antiviral interferon response and controlling inflammation are important therapeutic options to effectively eliminate SARS-CoV2 induced pathogenesis. Ongoing and future studies may provide additional evidence on their safety and efficacy to treat COVID-19 pathogenesis.
Mangroves of Maharashtra are under great threat of human enchroachment. The increased pressure over the mangrove habitat degrade the mangrove area. The Raigad district is close to the Mumbai and the activities in Mumbai have the reflections over the Raigad mangroves. In the present work attempt is made to analyse the area occupied by the mangroves in the coastal area of Raigad district and the changes in the mangrove habitat over the period of time using Google Earth Pro images and ground observations. The threats to the mangroves of Raigad were also analysed, it was observed that there is slight decline in the mangrove area in last ten years, 103.80 Km 2 in 2005 to 88.09 Km 2 in 2015. But, the mangroves are under great threat and continuous urabanization will lead into the destruction of this habitat.
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