Synthesis of Triazolo[4',5':4,5]furo[2,3-c]pyridine via Post Modification of an Unusual Groebke-Blackburn-Bienaymé Multicomponent Reaction.

The Groebke-Blackburn-Bienaymé (GBB) reaction is a well-established three-component reaction for synthesizing imidazofused scaffolds from heterocyclic amidines, aldehydes, and isonitriles. However, the replacement of pyridoxal as an aldehyde component in this reaction results in the formation of the furo[2,3-c]pyridine skeleton as an "unusual GBB product". Despite the interesting nature of this unusual reaction, not much work was further reported. The present research investigates the optimization strategy for the synthesis of novel tricyclic triazolo[4',5':4,5]furo[2,3-c]pyridines via diazotization of 2,3-diamino-furo[2,3-c]pyridines specifically synthesized utilizing the chemistry of tert-alkyl isocyanide.

Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism.

The calcium sensing receptor (CaSR) plays an important role in maintaining calcium homeostasis. The use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, cinacalcet has limitations due to its high cLogP and pKa. A systematic optimization of cinacalcet to reduce its cLogP and pKa yielded compound 23a (LNP1892). Compound 23a showed excellent potency and a favorable pharmacokinetics profile, and lacked the liabilities of cinacalcet, making it a highly differentiated precision calcimimetic. In adenine-diet-induced chronic kidney disease (CKD) models, 23a demonstrated robust and dose-dependent efficacy, as measured by plasma parathyroid hormone (PTH) levels. It also showed an excellent safety profile in animal studies. Phase 1 clinical trials with 23a in healthy volunteers confirmed its excellent safety, tolerability, and effectiveness in lowering PTH levels in a dose-dependent manner, without causing symptomatic hypocalcaemia. Encouraged by these promising results, LNP1892 was taken to a Phase 2 study in CKD patients.

Diversity in the ligand binding pocket of HapR attributes to its uniqueness towards several inhibitors with respect to other homologues - A structural and molecular perspective.

Vibrio cholerae is a prolific bacterium. Cumulative studies clearly demonstrate the key role of quorum sensing on the lifecycle of this bacterium. Of the sensory network components, HapR is known as high cell density master regulator. Until now, no information is available on native HapR ligand despite the protein having a ligand binding pocket. Interestingly, function of SmcR, a HapR homologue of Vibrio vulnificus is inhibited by a small molecule Qstatin. Structural analysis of SmcR with Qstatin identifies key interacting residues in SmcR ligand binding domain. Despite bearing significant homology with SmcR, HapR function remained unabated by Qstatin. Sequence alignment indicates divergence in the key residues of ligand binding pocket between these two regulators. A series of ligand binding domain mutants of HapR was constructed where only HapR quadruple mutant responded to Qstatin and newly synthesized IMT-VC-212. Crystal structure analysis revealed four key residues are responsible for changes in the volume of ligand binding pocket of HapR quadruple mutant compared to the wild type counterpart, thereby increasing the accessibility of Qstatin and its derivative in case of the former. The mechanistic insights exuberating from this study will remain instrumental in designing inhibitors against wild type HapR.

One-Pot Domino Reaction: Direct Access to Polysubstituted 1,4-Benzothiazine 1,1-Dioxide via Water-Gas Shift Reaction Utilizing DMF/H2O.

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.

Free spermidine evokes superoxide radicals that manifest toxicity.

Spermidine and other polyamines alleviate oxidative stress, yet excess spermidine seems toxic to Escherichia coli unless it is neutralized by SpeG, an enzyme for the spermidine N-acetyl transferase function. Thus, wild-type E. coli can tolerate applied exogenous spermidine stress, but ΔspeG strain of E. coli fails to do that. Here, using different reactive oxygen species (ROS) probes and performing electron paramagnetic resonance spectroscopy, we provide evidence that although spermidine mitigates oxidative stress by lowering overall ROS levels, excess of it simultaneously triggers the production of superoxide radicals, thereby causing toxicity in the ΔspeG strain. Furthermore, performing microarray experiment and other biochemical assays, we show that the spermidine-induced superoxide anions affected redox balance and iron homeostasis. Finally, we demonstrate that while RNA-bound spermidine inhibits iron oxidation, free spermidine interacts and oxidizes the iron to evoke superoxide radicals directly. Therefore, we propose that the spermidine-induced superoxide generation is one of the major causes of spermidine toxicity in E. coli.

Role of toll-like receptor 7/8 pathways in regulation of interferon response and inflammatory mediators during SARS-CoV2 infection and potential therapeutic options.

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.

Terminal Respiratory Oxidases: A Targetables Vulnerability of Mycobacterial Bioenergetics?

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.

Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

Efficient synthesis of (+)-1,8,8a-tri-epi-swainsonine, (+)-1,2-di-epi-lentiginosine, (+)-9a-epi-homocastanospermine and (-)-9-deoxy-9a-epi-homocastanospermine from a D-glucose-derived aziridine carboxylate, and study of their glycosidase inhibitory activities.

The utility of a D-glucose-derived aziridine carboxylate was demonstrated for the synthesis of polyhydroxylated quinolizidine and indolizidine alkaloids. The chemoselective reduction of 1 followed by two-carbon homologation by the Wittig reaction afforded gamma,delta-aziridino-alpha,beta-unsaturated ester 9, which on regioselective nucleophilic aziridine ring opening either by using water as a nucleophile or hydrogenation afforded delta-lactams 11/16--true synthons for the synthesis of four structurally different iminosugars, namely quinolizidine alkaloids 5b/5c, swainsonine 6b and lentiginosine 7b analogues. Glycosidase inhibitory activities of these iminosugars were investigated.

An efficient synthesis of D-erythro- and D-threo-sphingosine from D-glucose: olefin cross-metathesis approach.

[reaction: see text] The D-erythro- and D-threo-sphingosine were synthesized via E-selective olefin cross-metathesis using a D-glucose-derived building block and long-chain terminal alkene.

Aziridine carboxylate from D-glucose: synthesis of polyhydroxylated piperidine, pyrrolidine alkaloids and study of their glycosidase inhibition.

The D-glucose derived aziridine carboxylate 5 was obtained from (E)-ethyl-6-bromo-1,2-O-isopropylidene-3-O-benzyl-5-deoxy-alpha-D-xylo-5-eno-heptofuranuronate 4 through conjugate addition of benzylamine and in situ intramolecular nucleophilic expulsion of bromine. The regioselective aziridine ring-opening, using water as a nucleophile, resulted in the alpha-hydroxy-beta-aminoester 6, which was exploited in the synthesis of six and five membered azasugars 1b/1c and 2b/2c, respectively. The glycosidase inhibitory activity of the title compounds was evaluated.