p-TsOH-Mediated Intramolecular C2-Arylation on NH-Indoles: Access of 5,10-Dihydroindeno[1,2-b]indoles.

5,10-Dihydroindeno[1,2-b]indole has served as an important starting precursor for BARAC-fluor reagent in medicinal chemistry. Herein, an unprecedented p-TsOH assisted intramolecular C2-arylation of NH-indoles via C(sp2)-CN/C(sp2)-H coupling, offering a series of 5,10-dihydroindeno[1,2-b]indoles with moderate to good yields, has been showcased under redox-neutral conditions. Furthermore, successful scalability and synthetic applications highlight the practical nature of the method.

Copper/Zinc-Catalyzed Stitching of 2-Carbonylanilines with Bis(ynamides): Access to Pyrrolo[2,3-b]quinolines and Its Photophysical Studies.

Herein, a one-pot desulfonylative protocol enabled by copper(II)/zinc(II) salts to access pyrrolo[2,3-b]quinolines in good to excellent yields from 2-carbonylanilines and ynamide-derived buta-1,3-diynes has been reported. Significantly, various 2-carbonylanilines carrying reactive functional groups are well tolerated. Moreover, a gram-scale synthesis and synthetic application highlight the practical utility of the current protocol. Notably, the fluorescence properties of pyrrolo[2,3-b]quinolines have been recorded, and their potential use as a fluorescent probe in the imaging of live cells has been demonstrated.

Insights on discovery, efficacy, safety and clinical applications of ghrelin receptor agonist capromorelin in veterinary medicine.

Growth hormone and insulin like growth factor-1 plays an important role in the regulation of body composition and metabolism. Growth Hormone is released from the pituitary through a specific G-protein coupled receptor (GPCR) called growth hormone secretagogue receptor 1a expressed in the hypothalamus. Ghrelin is a peptide hormone released from the cells in the stomach, which stimulates appetite and food intake in mammals, regulates gut motility, gastric acid secretion, taste sensation, circadian rhythm, learning and memory, oxidative stress, autophagy, glucose metabolism etc. When the release of the endogenous ligand GHSR-1a, i.e., ghrelin is malfunctioned or stopped, external substitutes are administrated to induce the stimulation of growth hormone and appetite. A class of compound known as ghrelin receptor agonists are developed as an external substitute of ghrelin for regulation and stimulation of growth hormone in frailty, for body weight gain, muscle mass gain, prevention of cachexia and for the treatment of chronic fatigue syndromes. Capromorelin [Entyce™ (Aratana Therapeutics, Leawood, KS, USA)] is the only FDA (Food and Drug Administration) approved (May 2016) drug used for stimulating appetite in dogs and was marketed in the fall of 2017. In 2020, USFDA approved Capromorelin [Elura™ (Elanco US Inc.)] for the management of weight loss in chronic kidney disease of cats. This article reviews the discovery of the ghrelin receptor agonist capromorelin, its efficacy, safety, clinical applications and aims to delineate its further scope of use in veterinary practice.

Twofold Heteroannulation Reactions Enabled by Gold(I)/Zinc(II) Catalysts: Synthesis of Amine-Substituted Diaryl[c,h][1,6]naphthyridines.

A straightforward and atom-economical one-pot protocol catalyzed by gold(I) and zinc(II) for the synthesis of amine-substituted diaryl[c,h][1,6]naphthyridines from two different aromatic nitriles has been showcased. This dual-catalytic strategy is highly efficient, offering an array of tetracyclic heteroaromatic products in good to excellent yields. Furthermore, the base can efficiently catalyze the second annulation step, yielding structurally unique thiophene-fused [1,6]naphthyridines in good yields.

Leveraging Zn(II) Catalyst: Synthesis of Amidoquinolines via (3 + 3) Heteroannulation of Aromatic Amines and Ynamides.

Herein, we present a Zn(II)-catalyzed (3 + 3) heteroannulation reaction between aromatic amines and 1,3-diynamides for the synthesis of amidoquinolines. A large number of aromatic amines are well tolerated, furnishing quinoline derivatives in up to excellent yield. Notably, various reactive functional groups have survived under the optimal reaction conditions, highlighting the mildness of the developed protocol. In addition, amines derived from bioactive molecules show modest reactivity.

Nitrogen Atom Transfer Enables the (5+1) Annulation Reaction to Access Aminoisoquinolines.

Herein, a catalytic synthetic transformation offering a series of -NH2 group-bearing aminoisoquinolines with moderate to good yields has been showcased. Interestingly, the nitrogen atom of the isoquinoline ring is coming from the reaction medium upon metal-assisted C≡N bond cleavage. Moreover, this (5+1) annulation reaction shows broad substrate variation. Furthermore, the derivatization of the isoquinoline core via functional group interconversions and mechanistic studies to identify the reaction intermediate have been carried out successfully.

Sequential Cu(II)-Catalyzed Multicomponent C-N Coupling, Nucleophilic Addition, and Cyclization Cascade: A Diastereoselective Approach to Carboxamide-Embedded Hexahydrobenzofuran Core.

Cascade or domino reactions serve as a powerful technique for the synthesis of complex organic scaffolds in one pot. Herein, a Cu(II)-catalyzed and silica gel-assisted multicomponent reaction (MCR) between bromoalkyne-tethered cyclohexadienones, amides, and water for the construction of hexahydrobenzofuran-3-carboxamide is developed. The reaction proceeds via a C-N coupling reaction followed by hydrative cyclization of ynamide intermediates. Notably, good to excellent diastereoselectivity is complementary of this reaction.

Cu(II)-catalyzed [4 + 1] and [4 + 3] annulation reactions: a modular approach to N-aryl/alkyl substituted 2,5-diamidopyrroles and diazepines.

A one-pot copper-catalyzed [4 + 1] annulation reaction of primary amines with ynamide-derived buta-1,3-diynes for the synthesis of 2,5-diamido bearing N-aryl/alkyl pyrroles in up to excellent yields has been showcased. A broad range of primary amines having highly reactive functional groups are well tolerated. Notably, sterically demanding aniline and primary aliphatic amines are excellent amine sources. Furthermore, the current protocol may yield structurally unique diazepine derivatives. The scale-up reaction and fruitful chemical elaboration of pyrrole motifs highlight the importance of this reaction.

Synergetic copper/zinc catalysis: synthesis of aryl/heteroaryl-fused 1H-pyrrolo[3,2-c]pyridines.

Scaffolds having a 1H-pyrrolo[3,2-c]pyridine core show significant biological activity. Herein, we report a synergetic copper/zinc-catalyzed one-step annulation reaction of 2-amino (hetero)arylnitriles with ynamide-derived buta-1,3-diynes to deliver 1H-pyrrolo[3,2-c]quinoline-2,4-diamine derivatives in moderate to good yields. The annulation reaction follows a double cyclization pathway. The gram-scale synthesis of 1H-pyrrolo[3,2-c]quinoline-2,4-diamine proves the practicality of this protocol.

Phase III, Randomized, Double-blind, Placebo controlled trial of Efficacy, Safety and Tolerability of Antiviral drug Umifenovir vs Standard care of therapy in non-severe COVID-19 patients.

OBJECTIVE: To test efficacy, safety and tolerability of Umifenovir in non-severe COVID-19 adult patients. METHODS: We carried out randomized, double-blind, placebo-controlled, multicenter, phase III trials involving adult (18-75 years), non-severe COVID19 patients, randomized 1:1 on placebo or Umifenovir (800 mg BID, maximum 14 days) respectively along with standard-of-care. The primary endpoint for Asymptotic-mild patients was time to nasopharyngeal swab RT-PCR test negativity. For Moderate patients, the average change in the ordinal scale from the baseline scores on the eight-point WHO ordinal scale was assessed. RESULTS: 132 patients were recruited between 3rd October to 28th April 2021, of which 9 discontinued due to various reasons. In Mild-asymptomatic patients (n=82), we found that 73% patients in the Umifenovir arm were RT-PCR negative, while 40% patients in the placebo arm were negative (P=0.004) on day 5. However, in the moderate group (n=41), the WHO scores for the Umifenovir arm was not statistically significant (P=0.125 on day 3), while it was statistically significant in the Mild-asymptomatic group (P=0.019 on day 5). CONCLUSION: Umifenovir meets the primary and secondary endpoint criteria and exhibits statistically significant efficacy for Mild-asymptomatic patients. It is efficacious, safe and well-tolerated at the tested dosage of 800mg BID, maximum 14 days.

Gold-catalyzed homo- and cross-annulation of alkynyl carboxylic acids: a facile access to substituted 4-hydroxy 2H-pyrones and total synthesis of pseudopyronine A.

A Au(i)-catalyzed homo- and cross-annulation reaction of alkynyl carboxylic acids offering 3,6-disubstituted 4-hydroxy 2H-pyrones has been demonstrated. The reaction tolerates various substituted alkynyl carboxylic acids and moderate to good yields of α-pyrone scaffolds have been observed. Later, a gram-scale reaction of the acid and the total synthesis of the natural product pseudopyronine A have been carried out successfully.

Solvent Effect in Gold(I)-Catalyzed Domino Reaction: Access to Furopyrans.

We report an efficient synthesis of furopyrans through a gold(I)-catalyzed domino reaction. By starting from the same source and changing the solvent of the reaction, two classes of furopyrans are accessible. During this one-step process, which takes place in DMF, two bonds and two heterocycles are formed. DFT calculations furnish the mechanistic understanding of this transformation. The sequence includes a 5-endo-dig cyclization, a regioselective 8-endo-dig cyclization, and a retro 8π and a 6π electrocyclization.

Gold(I)-Catalyzed Synthesis of Furopyrans: Insight into Hetero-Diels-Alder Reactions.

We report herein the synthesis of complex molecules containing furopyran cores through a gold(I)-catalyzed hetero-Diels-Alder cascade reaction. During this process, the diene and the dienophile are produced concomitantly by the action of a single catalyst from a single starting material. Moreover, six bonds, four heterocycles, and four controlled stereogenic centers are formed in a one-step operation. DFT calculations provide the mechanistic basis of this unprecedented reaction.

p-TsOH Promoted Au(I)-Catalyzed Consecutive Endo Cyclization of Yne-Tethered Ynamide: Access to Benzofused Dihydroisoquinolones.

A novel synthetic route to benzo[f]dihydroisoquinolone through a p-TsOH promoted cascade cyclization of easily accessible diyne-tethered ynamides in the presence of a Au(I)-catalyst is described. This reaction unveils a broad substrate scope, constructing a wide range of benzo[f]dihydroisoquinolones in good yields. The diyne-tethered ynamides are synthesized from inexpensive o-iodoaniline through Sonogashira couplings and the Cu-mediated C-N bond formation. The role of p-TsOH is examined, and the reaction pathway is also deduced. The benzo[f]isoquinoline scaffold is constructed from benzo[f]dihydroisoquinolones.

Access to cyclobutene-fused azepines through Au-catalyzed cycloisomerization of stable alkyne tethered ketene N,N-acetals.

A base promoted reaction between N-protected propargyl amines and 3-bromopropiolate readily provides an array of novel stable alkyne-tethered ketene N,N-acetals in good yields. A wide range of structurally complex cyclobutene-fused azepine heterocycles are synthesized through the gold-catalyzed intramolecular cycloisomerization of ketene N,N-acetals for the first time. A plausible reaction pathway is deduced on the basis of the (1)H NMR studies.

Regioselective hydration of terminal halo-substituted propargyl carboxylates by gold catalyst: synthesis of α-acyloxy α'-halo ketones.

Regioselective hydration of the terminal halo-substituted propargyl carboxylate by gold(I) catalyst is reported. The mild catalytic conditions tolerate common acid-labile protecting groups, and a wide variety of α-acyloxy α'-halo ketones are efficiently synthesized within a short reaction time. The α-acyloxy α'-halo ketones are used for the synthesis of 2-aminothiazoles.

Gold-catalyzed regioselective hydration of propargyl acetates assisted by a neighboring carbonyl group: access to α-acyloxy methyl ketones and synthesis of (±)-actinopolymorphol B.

A general atom-economical approach for the synthesis of α-acyloxy methyl ketone is demonstrated through regioselective hydration of a wide range of propargyl acetates. Readily available catalyst comprising of 1% Ph(3)PAuCl and 1% AgSbF(6) in dioxane-H(2)O efficiently hydrolyzes the terminal alkynes of the propargyl acetate in the absence of acid promoters at ambient temperature within a short time. Effective regioselective hydration is facilitated by the neighboring carbonyl group as demonstrated through (18)O-labeling study. Compatibility of functional moieties and tolerance to various acid-labile protecting groups are observed. The catalytic condition is also suitable to perform hydration of TMS-substituted propargyl acetates, even though it requires prolonged reaction time for completion. Stereointegrity of the propargylic acetate is preserved during the hydration. The robustness of the system is successfully demonstrated through gram scale preparation of the product in nearly quantitative yield. The common α-acyloxy methyl ketone is transformed to 1,2-diol and 1,2-amino alcohol derivatives. Synthesis of actinopolymorphol B is achieved for the first time involving hydration of the propargyl acetate as the key step.