Direct esterification of amides by the dimethylsulfate-mediated activation of amide C-N bonds.

Amides are important intermediates in organic chemistry and the pharmaceutical industry, but their low reactivity requires catalysts and/or severe reaction conditions for esterification. Here, a novel approach was devised to convert amides into esters without the use of transition metals. The method effectively overcomes the inherent low reactivity of amides by employing dimethylsulfate-mediated reaction to activate the C-N bonds. To confirm the proposed reaction mechanism, control experiments and density functional theory (DFT) calculations were conducted. The method demonstrates a wide array of substrates, including amides with typical H/alkyl/aryl substitutions, N,N-disubstituted amides, amides derived from alkyl, aryl, or vinyl carboxylic acids, and even amino acid substrates with stereocentres. Furthermore, we have shown the effectiveness of dimethylsulfate in removing acyl protective groups in amino derivatives. This study presents a method that offers efficiency and cost-effectiveness in broadening the esterification capabilities of amides, thereby facilitating their increased utilization as synthetic compounds in diverse transformations.

Improved and ligand-free copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from o-bromoarylamine and nitriles.

We present an improved copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from o-bromoarylamine and nitriles, under mild and ligand-free conditions. The optimal conditions yielded exceptional products of up to 98%, demonstrating the broad applicability of this synthetic strategy in generating a wide range of valuable imidazole derivatives. This methodology enables the efficient synthesis of various substituted benzimidazole derivatives and offers an environmentally friendly alternative to conventional methods. By eliminating the use of harsh reagents and high temperatures associated with traditional synthesis approaches, this method proves to be more efficient and robust. Notably, we successfully applied this synthetic approach to the synthesis of bendazol and thiabendazole, yielding 82% and 78%, respectively, on a 100 gram scale.

Facile Synthesis of Benzimidazoles via N-Arylamidoxime Cyclization.

A facile synthesis of benzimidazoles was described by a one-pot process containing acylation-cyclization of N-arylamidoxime. This method provided an alternative synthesis of benzimidazoles with a certain diversity of substituted groups in acceptable yields (up to 96%). More importantly, the construction of bis-benzimidazole (8), the key intermediate for making telmisartan, was achieved by adopting this method that enabled avoiding the undesired nitration with nitric/sulfuric acid and the cyclization in polyphosphoric acid in the existing operations.

Practical and Highly Efficient Synthesis of Remdesivir from GS-441524.

A three-step sequence for preparing remdesivir, an important anti-SARS-CoV-2 drug, is described. Employing N,N-dimethylformamide dimethyl acetal (DMF-DMA) as a protecting agent, this synthesis started from (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-furan-2-carbonitrile (GS-441524) and consisted of three reactions, including protection, phosphoramidation, and deprotection. The advantages of this approach are as follows: (1) the protecting group could be removed under a mild deprotection condition, which avoided the generation of the degraded impurity; (2) high stereoselectivity was achieved in the phosphorylated reaction; (3) this synthesis could be performed successively without purification of intermediates. Moreover, the overall yield of this approach on a gram scale could be up to 85% with an excellent purity of 99.4% analyzed by high-performance liquid chromatography (HPLC).

Synthesis and biological evaluation of artemisinin derivatives as potential MS agents.

In this paper, a series of artemisinin derivatives were synthesized and evaluated. Studies have shown that IFN-γ produced by Th1 CD4+ T cells and IL-17A secreted by Th17 CD4+ T cells played critical roles in the treatment of multiple sclerosis. We used different concentrations of artemisinin derivatives to inhibit Th1 / Th17 differentiation in naive CD4+ T cells and to characterize IFN-γ / IL-17A in in vitro experiments. The preliminary screening results showed that ester compound 5 exhibited obvious inhibitory activities on Th1 and Th17 (IFN-γ decreased from 41% to 3% and IL-17A decreased from 24% to 8% at the concentration of 10 nM to 10 µM), and carbamate compounds also had obvious inhibitory activities against Th17 at high concentration. Moreover, we investigated the effect of compound 5 on myelin oligodendrocyte glycoprotein (MOG)-induced mice experimental autoimmune encephalomyelitis (EAE) model in vivo. 100 mg/kg compound 5 effectively reduced the disease severity of EAE compared with the vehicle group. This research revealed that compound 5 could be a promising avenue as potential MS inhibitor.

Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2.

The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.

Histopathological features for coexistent invasive cancer in large colorectal adenomatous polyps.

BACKGROUND: Histopathological features associated with coexistent invasive adenocarcinoma in large colorectal adenomas have not been described. This study aimed to determine the association of histopathological features in areas of low-grade dysplasia with coexistent invasive adenocarcinoma. METHODS: High-grade lesions (containing high-grade dysplasia or adenocarcinoma) from a cohort of large (at least 20 mm) colorectal adenomas removed by endoscopic resection were subjected to detailed histopathological analysis. The histopathological features in low-grade areas with coexistent adenocarcinoma were reviewed and their diagnostic performance was evaluated. RESULTS: Seventy-four high-grade lesions from 401 endoscopic resections of large adenomas were included. In the low-grade dysplastic areas, a coexistent invasive adenocarcinoma was associated significantly with a cribriform or trabecular growth pattern (P < 0.001), high nuclear grade (P < 0.001), multifocal intraluminal necrosis (P < 0.001), atypical mitotic figures (P = 0.006), infiltrative lesion edges (P < 0.001), a broad fibrous band (P = 0.001), ulceration (P < 0.001), expansile nodules (P < 0.001) and an extensive tumour-infiltrating lymphocyte pattern (P = 0.04). Lesions with coexistent invasive adenocarcinoma harboured at least one of these features. The area under the receiver operating characteristic curve (AUROC) for coexistent invasive adenocarcinoma, using frequencies of adverse histopathological factors in low-grade areas, was 0.92. The presence of two or more of these adverse histopathological features in low-grade areas had a sensitivity of 86 per cent and a specificity of 84 per cent for coexistent invasive adenocarcinoma. CONCLUSION: Several histopathological features in low-grade dysplastic areas of adenomas could be predictive of coexistent adenocarcinoma.

Synthesis and anticancer activity of ethyl 5-amino-1-N-substituted-imidazole-4-carboxylate building blocks.

A series of 5-amino-1-N-substituted-imidazole-4-carboxylate building blocks was synthesized and assayed for their antiproliferative potential against human cancer cell lines, including HeLa (cervical), HT-29, HCT-15 (colon), A549 (lung), and MDA-MB-231 (breast) cells. The preliminary screening results revealed that several derivatives containing alkyl chains at the N-1 position of the imidazole core demonstrate a certain inhibitory effect on growth and proliferation. A significant effect was observed following ethyl 5-amino-1-dodecyl-1H-imidazole-4-carboxylate (5e) treatment for 72 h. The IC50 value for HeLa cells was 0.737 ± 0.05 µM, whereas that for HT-29 cells was 1.194 ± 0.02 µM. Further investigations revealed that 5e significantly inhibited tumor cell colony formation and migration, and it exhibited antiadhesive effects on HeLa cells as well as antitubulin activity along with the induction of early apoptosis of HeLa and HT-29 cells. In addition, derivative 5e significantly reduced the cell mitochondrial membrane potential in a dose-dependent manner and induced early apoptosis of HeLa and HT-29 cells, indicating that 5e may serve as a lead compound for further drug discovery and development.

Weinreb Amide Approach to the Practical Synthesis of a Key Remdesivir Intermediate.

Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from 2,3,5-tri-O-benzyl-d-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection, and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable production of the key remdesivir intermediate.

Structural basis for repurpose and design of nucleoside drugs for treating COVID-19

SARS-CoV-2 has caused a global pandemic of COVID-19 that urgently needs an effective treatment. Nucleoside analog drugs including favipiravir have been repurposed for COVID-19 despite of unclear mechanism of their inhibition of the viral RNA polymerase (RdRp). Here we report the cryo-EM structures of the viral RdRp in complex with favipiravir and two other nucleoside inhibitor drugs ribavirin and penciclovir. Ribavirin and the ribosylated form of favipiravir share a similar ribose scaffold that is distinct from penciclovir. However, the structures reveal that all three inhibitors are covalently linked to the primer strand in a monophosphate form despite the different chemical scaffolds between favipiravir and penciclovir. Surprisingly, the base moieties of these inhibitors can form mismatched pairs with the template strand. Moreover, in view of the clinical disadvantages of remdesivir mainly associated with its prodrug form, we designed several orally-available remdesivir parent nucleoside derivatives, including VV16 that showed 5-fold more potent than remdesivir in inhibition of viral replication. Together, these results demonstrate an unexpected promiscuity of the viral RNA polymerase and provide a basis for repurpose and design of nucleotide analog drugs for COVID-19. One Sentence SummaryCryo-EM structures of the RNA polymerase of SARS-CoV-2 reveals the basis for repurposing of old nucleotide drugs to treat COVID-19.

Synthesis of CBD and Its Derivatives Bearing Various C4'-Side Chains with a Late-Stage Diversification Method.

A novel synthetic route for making (-)-CBD and its derivatives bearing various C4'-side chains is developed by a late-stage diversification method. Starting from commercially available phloroglucinol, the key intermediate (-)-CBD-2OPiv-OTf is efficiently and regioselectively prepared and further undergoes Negishi cross-coupling to furnish (-)-CBD. This approach allowed an efficient synthesis of (-)-CBD in a five-step total 52% yield on a 10 g scale. Furthermore, diversification on the C4'-side chain with this method can be realized in a wide range.

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview.

The 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These five-membered heterocyclic motifs with three nitrogen heteroatoms can be prepared easily using 'click' chemistry with copper- or ruthenium-catalysed azide-alkyne cycloaddition reactions. Recently, the 'linker' property of 1,2,3-triazoles was demonstrated, and a novel class of 1,2,3-triazole-containing hybrids and conjugates was synthesised and evaluated as lead compounds for diverse biological targets. These lead compounds have been demonstrated as anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leishmanial, and neuroprotective agents. The present review summarises advances in lead compounds of 1,2,3-triazole-containing hybrids, conjugates, and their related heterocycles in medicinal chemistry published in 2018. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.

Oxidative Aromatization of 3,4-Dihydroquinolin-2(1 H)-ones to Quinolin-2(1 H)-ones Using Transition-Metal-Activated Persulfate Salts.

Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4-dihydroquinolin-2(1 H)-ones through the activation of readily available transition metals, such as iron and copper. The feasible protocol conforming to the requirement of green chemistry was utilized in the preparation of the key intermediate (7-(4-chlorobutoxy)quinolin-2(1 H)-one 2) of brexpiprazole in 80% isolated yield on a 100 g scale, and different quinolin-2(1 H)-one derivatives with various functional groups were demonstrated in 52-89% yields.

Endoscopic Resections in Inflammatory Bowel Disease: A Multicentre European Outcomes Study.

BACKGROUND AND AIMS: Inflammatory bowel disease is associated with an increased risk of colorectal cancer, with estimates ranging 2-18%, depending on the duration of colitis. The management of neoplasia in colitis remains controversial. Current guidelines recommend endoscopic resection if the lesion is clearly visible with distinct margins. Colectomy is recommended if complete endoscopic resection is not guaranteed. We aimed to assess the outcomes of all neoplastic endoscopic resections in inflammatory bowel disease. METHODS: This was a multicentre retrospective cohort study of 119 lesions of visible dysplasia in 93 patients, resected endoscopically in inflammatory bowel disease. RESULTS: A total of 6/65 [9.2%] lesions <20 mm in size were treated by ESD [endoscopic submucosal dissection] compared with 59/65 [90.8%] lesions <20 mm treated by EMR [endoscopic mucosal resection]; 16/51 [31.4%] lesions >20 mm in size were treated by EMR vs 35/51 [68.6%] by ESD. Almost all patients [97%] without fibrosis were treated by EMR, and patients with fibrosis were treated by ESD [87%], p < 0.001. In all, 49/78 [63%] lesions treated by EMR were resected en-bloc and 27/41 [65.9%] of the ESD/KAR [knife-assisted resection] cases were resected en-bloc, compared with 15/41 [36.6%] resected piecemeal. Seven recurrences occurred in the cohort. Seven complications occurred in the cohort; six were managed endoscopically and one patient with a delayed perforation underwent surgery. CONCLUSIONS: Larger lesions with fibrosis are best treated by ESD, whereas smaller lesions without fibrosis are best managed by EMR. Both EMR and ESD are feasible in the management of endoscopic resections in colitis.

Qualitative analysis of Schizonepeta annua (Pall.) Schischk essential oil by gas chromatography-quadrupole time-of-flight mass spectrometry.

In this study, a method for the qualitative analysis of small molecular compounds in Schizonepeta annua (Pall.) Schischk essential oil was established based on gas chromatography-quadrupole time-of-flight mass spectrometry. In addition to an automated search of the NIST library, the identification of oxygenated monoterpenes, phenolic esters, and phenolic compounds was achieved by two additional strategies. One strategy involved comparing the relative errors of accurate masses measured for ions in the experimental spectra with those calculated for fragments identified from the NIST database of candidate matches. The second strategy involved combination of the product ion scans and positive chemical ionisation spectra for structural elucidation. Overall, 95.45% of the total essential oil volatile chemical content of Schizonepeta annua (Pall.) Schischk was identified, with phenolic monoterpenes dominating.

Phenotypic identification of Penicillium spp. isolated from clinical wastes based on microstructure characteristics

@#Aims: The present study aimed to recognize the microstructure of conidiophores and spores of Penicilliumspp. which were isolated from clinical wastes. Methodology and results:The isolates of Penicilliumspp. were obtained from the solid clinical wastes on V8A medium and purified by single spore method. The culture characteristics were described in five culture media included; Czapek Yeast Extract Agar(CYA); Malt Extract Agar (MEA), Potato Dextrose Agar (PDA), Sabouraud Dextrose Agar (SDA) and Czapek-Dox Agar(CZ) while the conidiophores and spores were described using light and Scanning Electronic Microscope (SEM).Penicilliumspp. observedsome differences in their culture characteristics. Among 11 Penicilliumspecies isolated in this study and identified based on culture and microscope morphology. Five species including P. simplicissium,P. waksmanii,P. corylophilum andP. decumbensas well as one species identified as T. wortmanniiwere described in detailusing SEM. Conclusion, significance and impact of study:The study revealed that the microstructure of the fungal spores and conidiophores play an important role in the taxonomy of fungi species based on the phenotypic method.

2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry.

2-Aminothiophenes are important five-membered heterocyclic building blocks in organic synthesis, and the chemistry of these small molecules is still developing based on the discovery of cyclization by Gewald. Another attractive feature of 2-aminothiophene scaffolds is their ability to act as synthons for the synthesis of biological active thiophene-containing heterocycles, conjugates and hybrids. Currently, the biological actions of 2-aminothiophenes or their 2-N-substituted analogues are still being investigated because of their various mechanisms of action (e.g., pharmacophore and pharmacokinetic properties). Likewise, the 2-aminothiophene family is used as diverse promising selective inhibitors, receptors, and modulators in medicinal chemistry, and these compounds even exhibit effective pharmacological properties in the various clinical phases of appropriate diseases. In this review, major biological and pharmacological reports on 2-aminothiophenes and related compounds have been highlighted; most perspective drug-candidate hits were selected for discussion and described, along with additional synthetic pathways. In addition, we focused on the literature dedicated to 2-aminothiophenes and 2-N-substituted derivatives, which have been published from 2010 to 2017.

L-DOPA inhibits excitatory synaptic transmission in the rat nucleus tractus solitarius through release of dopamine.

The mode of action of L-DOPA on excitatory synaptic transmission in second-order neurons of the nucleus tractus solitarius (NTS) was studied using the rat brainstem slices. Superfusion of L-DOPA (10µM) reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without any effect on the amplitude. A low concentration (1µM) was ineffective on the mEPSCs, and the highest concentration (100µM) exerted a stronger inhibitory effect. L-DOPA (10µM) decreased the amplitude of EPSCs (eEPSCs) evoked by electrical stimulation of the tractus solitarius and increased the paired-pulse ratio. The inhibitory effects of L-DOPA on mEPSCs and eEPSCs were similar to those of dopamine (100µM). The effects of L-DOPA were blocked by a competitive antagonist, L-DOPA methyl ester (100µM) and also by a D2 receptor antagonist, sulpiride (10µM), while those of dopamine were blocked by the latter but not by the former. In reserpine (5mg/kg, s.c.)-treated rats, the effects of L-DOPA on both mEPSCs and eEPSCs were completely abolished, but those of dopamine remained unchanged. The present results suggest a possibility that L-DOPA may induce the release of dopamine from the axon terminals in the NTS and the released dopamine suppresses the glutamatergic transmission through activation of the presynaptic D2 receptors.

Upregulation of Melanogenesis and Tyrosinase Activity: Potential Agents for Vitiligo.

Melanin, the compound primarily responsible in humans for hair, eye and skin pigmentation, is produced by melanocytes through a complicated process called melanogenesis that is catalyzed by tyrosinase and other tyrosinase-related proteins. The abnormal loss of melanin causes dermatological problems such as vitiligo. Hence the regulation of melanogenesis and tyrosinase activity is very important for treating hypopigmentary disorders. Many melanogenesis stimulators have been discovered during the past decade. This article reviews recent advances in research on extracts and active ingredients of plants, synthesized compounds with stimulating effect on melanin synthesis and tyrosinase activity, as well as their influence on the expression of related proteins and possible signaling pathways for the design and development of novel anti-vitiligo agents.