The rapid construction and biological evaluation of densely substituted pyrrolo[1,2-a]indoles via a BF3·OEt2-assisted cascade approach.

Lewis-acid cascade reactions promoted by BF3·OEt2 are reported for the synthesis of highly substituted pyrrolo[1,2-a]indoles and congeners of benzofuro[2,3-b]indoles. These reactions are highly regio- and diastereoselective towards generating up to five contiguous stereogenic centers, including two vicinal quaternary centers. Furthermore, an established cascade approach and the mechanism proposed herein are well supported by quantum chemistry calculations. In addition, a self-dimerization intermediate was trapped and isolated to establish a strategy for potential access to both pyrrolo and benzo indole derivatives, leaving sufficient freedom for broadening. Furthermore, in-silico molecular docking and all atomistic molecular dynamic (MD) simulation analysis suggests that the synthesized pyrrolo[1,2-a]indole derivatives stably bind at the active site of the mycobacterial secreted tyrosine phosphatase B (MptpB) enzyme, an emerging anti-mycobacterial drug target. Deep learning-based affinity predictions and MMPBGBSA-based energy calculations of the docked poses are presented herein.

[RhCp*Cl2]2-Catalyzed Indole Functionalization: Synthesis of Bioinspired Indole-Fused Polycycles.

Polycyclic fused indoles are ubiquitous in natural products and pharmaceuticals due to their immense structural diversity and biological inference, making them suitable for charting broader chemical space. Indole-based polycycles continue to be fascinating as well as challenging targets for synthetic fabrication because of their characteristic structural frameworks possessing biologically intriguing compounds of both natural and synthetic origin. As a result, an assortment of new chemical processes and catalytic routes has been established to provide unified access to these skeletons in a very efficient and selective manner. Transition-metal-catalyzed processes, in particular from rhodium(III), are widely used in synthetic endeavors to increase molecular complexity efficiently. In recent years, this has resulted in significant progress in reaching molecular scaffolds with enormous biological activity based on core indole skeletons. Additionally, Rh(III)-catalyzed direct C-H functionalization and benzannulation protocols of indole moieties were one of the most alluring synthetic techniques to generate indole-fused polycyclic molecules efficiently. This review sheds light on recent developments toward synthesizing fused indoles by cascade annulation methods using Rh(III)-[RhCp*Cl2]2-catalyzed pathways, which align with the comprehensive and sophisticated developments in the field of Rh(III)-catalyzed indole functionalization. Here, we looked at a few intriguing cascade-based synthetic designs catalyzed by Rh(III) that produced elaborate frameworks inspired by indole bioactivity. The review also strongly emphasizes mechanistic insights for reaching 1-2, 2-3, and 3-4-fused indole systems, focusing on Rh(III)-catalyzed routes. With an emphasis on synthetic efficiency and product diversity, synthetic methods of chosen polycyclic carbocycles and heterocycles with at least three fused, bridged, or spiro cages are reviewed. The newly created synthesis concepts or toolkits for accessing diazepine, indol-ones, carbazoles, and benzo-indoles, as well as illustrative privileged synthetic techniques, are included in the featured collection.

A Catecholaldimine-Based NiII-Complex as an Effective Catalyst for the Direct Conversion of Alcohols to trans-Cinnamonitriles and Aldehydes.

A nickel(II) complex [Ni(HL)2] 1 was synthesized by treatment of a new catecholaldimine-based ligand with NiCl2·6H2O in methanol at room temperature. Complex 1 showed excellent catalytic activity where aromatic and heterocyclic alcohols were rapidly converted into trans-cinnamonitrile in a one-pot manner via oxidative olefination in the presence of KOH. The potential of the disclosed catalyst and the results obtained for the direct conversion of alcohols to two different functionalities (trans-cinnamonitrile and aldehydes) are well supported by DFT studies.

Design, Synthesis, and Applications of a Vanadium Complex: An Effective Catalyst for the Direct Conversion of Alcohols and Aldehydes to Esters.

A novel bench-stable V-catalyst [(L2)VIVO](ClO4) was synthesized and characterized by X-ray diffraction (XRD) analysis and FT-IR, UV-visible, and EPR spectroscopies, which confirmed its excellent catalytic activity. In application, aldehydes are rapidly converted into their corresponding esters without additives in a one-pot manner using a newly developed catalyst [(L2)VIVO](ClO4) and H2O2 as a green oxidant. The developed method is compatible with a broad range of densely substituted aldehydes and allows for the facile preparation of aliphatic, aromatic, and heterocyclic esters, including esters derived from CD3OD, methanol, ethanol, iso-propanol, n-butanol, sec-butyl alcohol, and propargylic alcohol. Gratifyingly, numerous alcohols also directly converted to their corresponding esters in a one-pot manner. We disclose herein the direct conversion of two different functionalities (alcohols and aldehydes) into esters (33 examples) with satisfactory yields, showing the potential of the developed catalyst toward varied oxidative organic transformations in a one-pot manner.

Effective Synthesis and Biological Evaluation of Functionalized 2,3-Dihydrofuro[3,2-c]coumarins via an Imidazole-Catalyzed Green Multicomponent Approach.

For the first time, an eco-friendly and efficient one-pot green multicomponent approach has been described to synthesize functionalized trans-2,3-dihydrofuro[3,2-c]coumarins (DHFCs). In this synthesis, imidazole and water were used as the catalyst and solvent, respectively, under mild conditions. Applications of the developed catalytic process in a water medium revealed the outstanding activity, productivity, and broad functional group tolerance, affording a series of newly designed DHFC and derivatives in excellent yields (72-98%). Moreover, the human serum albumin (HSA) binding ability of the synthesized DHFC derivatives has been uncovered through the detailed in silico and in vitro-based structure-activity analysis. The ability to bind HSA, the most abundant serum protein, in the low micromolar ranges unequivocally reflects the suitable absorption, distribution, metabolism, and elimination profile of the synthesized compounds, which may further be envisaged for their therapeutic usage endeavors.

Effective Synthesis and Biological Evaluation of Natural and Designed Bis(indolyl)methanes via Taurine-Catalyzed Green Approach.

An ecofriendly, inexpensive, and efficient route for synthesizing 3,3'-bis(indolyl)methanes (BIMs) and their derivatives was carried out by an electrophilic substitution reaction of indole with structurally divergent aldehydes and ketones using taurine and water as a green catalyst and solvent, respectively, under sonication conditions. Using water as the only solvent, the catalytic process demonstrated outstanding activity, productivity, and broad functional group tolerance, affording the required BIM natural products and derivatives in excellent yields (59-90%). Furthermore, in silico based structure activity analysis of the synthesized BIM derivatives divulges their potential ability to bind antineoplastic drug target and spindle motor protein kinesin Eg5. The precise binding mode of BIM derivatives with the ATPase motor domain of Eg5 is structurally reminiscent with previously reported allosteric inhibitor Arry520, which is under phase III clinical trials. Nevertheless, detailed analysis of the binding poses indicates that BIM derivatives bind the allosteric pocket of the Eg5 motor domain more robustly than Arry520; moreover, unlike Arry520, BIM binding is found to be resistant to drug-resistant mutations of Eg5. Accordingly, a structure-guided mechanism of Eg5 inhibition by synthesized BIM derivatives is proposed.

Designing a Redox Noninnocent Phenalenyl-Based Copper(II) Complex: An Autotandem Catalyst for the Selective Oxidation of Polycyclic Aromatic Hydrocarbons (PAHs).

A square-planar [CuIIL] complex 1, based on the redox-active phenalenyl unit LH2 = 9,9'-(ethane-1,2-diylbis(azanediyl))bis(1H-phenalen-1-one), is prepared and structurally characterized by single-crystal X-ray diffraction analysis. Complex 1 crystallizes at room temperature with the P1 space group. The molecular structure of 1 reveals the presence of intriguing C-H···Cu intermolecular anagostic interactions of the order ∼2.7715 Å. Utilizing the presence of anagostic interactions and the free nonbonding molecular orbitals (NBMOs) of the closed-shell phenalenyl unit in 1, the oxidation reactions of some industrially important polycyclic aromatic hydrocarbons (PAHs) in the presence of the [CuIIL] complex under very mild conditions have been reported. The direct conversion of anthracene-9-carbaldehyde to 9,10-anthraquinone in one step concludes that the catalyst shows dual activity in the chemical transformations. This also includes the first report of a "single-step" catalytic transformation of pyrene-1-carbaldehyde to the synthetically difficult pyren-4-ol, a precursor for the synthesis of several novel fluorescent probes for cell imaging.

Design, Synthesis, and Biological Evaluation of Densely Substituted Dihydropyrano[2,3-c]pyrazoles via a Taurine-Catalyzed Green Multicomponent Approach.

An efficient taurine-catalyzed green multicomponent approach has been described for the first time to synthesize densely substituted therapeutic core dihydropyrano[2,3-c]pyrazoles. Applications of the developed synthetic strategies and technologies revealed the synthesis of a series of newly designed 1,4-dihydropyrano[2,3-c]pyrazoles containing isonicotinamide, spirooxindole, and indole moieties. Detailed in silico analysis of the synthesized analogues revealed their potential to bind wild-type and antibiotic-resistant variants of dihydrofolate reductase, a principal drug target enzyme for emerging antibiotic-resistant pathogenic Staphylococcus aureus strains. Hence, the synthesized dihydropyrano[2,3-c]pyrazole derivatives presented herein hold immense promise to develop future antistaphylococcal therapeutic agents.

Glucagon-like peptide-1 analogues and thyroid cancer: An analysis of cases reported in the European pharmacovigilance database.

WHAT IS KNOWN AND OBJECTIVE: The use of glucagon-like peptide-1 (GLP-1) analogues has been linked to the risk of thyroid cancer. Spontaneous reports can provide information about rare adverse events occurring after the time of marketing. Our objective was to detect, from the European pharmacovigilance database (EudraVigilance), a signal of thyroid cancer during GLP-1 analogues treatment in patients with diabetes. METHODS: Herein, we analysed all reports of thyroid cancer reported with GLP-1 analogues in EudraVigilance database from their first marketing authorization till 30 January 2020. A case/non-case method was used to assess the association between thyroid cancer and GLP-1 analogues, calculating proportional reporting ratios (PRRs) and their 95% confidence interval (CI) as a measure of disproportionality. The cases were identified with Medical Dictionary for Regulatory Activities (MedDRA) version 22.1. RESULTS AND DISCUSSION: There were 11 243 cases of thyroid cancer and related preferred terms (PTs) in the 6 665 794 reports recorded in EudraVigilance during the study period. GLP-1 analogues were involved in 236 cases. Exenatide, liraglutide and dulaglutide met the criteria to generate a safety signal, suggesting that thyroid cancer is reported relatively more frequently in association with these drugs than with other medicinal products. The association was strongest for liraglutide followed by exenatide with PRR of 27.5 (95% CI, 22.7-33.3) and 22.5 (95% CI, 17.9-28.3), respectively. Disproportionality was also observed for GLP-1 analogues and individual identified preferred term, that is thyroid cancer (N = 111), medullary thyroid cancer (N = 64) and thyroid neoplasm (N = 46) with PRR of 14.4 (95% CI, 11.8-17.4), 221.5 (95% CI, 155.7-315.1) and 35.5 (95% CI, 25.9-48.5), respectively. WHAT IS NEW AND CONCLUSIONS: Our findings showed disproportionality for thyroid cancer, medullary thyroid cancer and thyroid neoplasm in patients treated with GLP-1 analogues. We have found evidence from spontaneous reports that GLP-1 analogues are associated with thyroid cancer in patients with diabetes.

Efficacy and safety of empagliflozin in type 2 diabetes mellitus: a meta-analysis of randomized controlled trials.

OBJECTIVES: The prevalence of diabetes has increased in the recent decades and optimum glycemic control is required to reduce morbidity and mortality. We meta-analyzed randomized controlled trials in order to assess the efficacy and safety of empagliflozin compared to placebo in type 2 diabetes mellitus patients. METHODS: We included double-blind, placebo controlled trials of empagliflozin that evaluated glycemic efficacy and safety (10 mg or 25 mg) either as monotherapy or as add-on to existing diabetes pharmacotherapy. RESULTS: The results demonstrated significant improvements in HbA1c (SMD -0.929%, 95 % CI -1.064 to -0.793, for 10 mg and -1.064%, 95 % CI -1.184 to -0.944, for 25 mg) and FPG (SMD -0.929%, 95 % CI -1.064 to -0.793, for 10 mg and -1.064%, 95 % CI -1.184 to -0.944, for 25 mg) with empagliflozin monotherapy (n = 609) compared to placebo. Significant improvements in HbA1c [SMD -1.582%, 95% CI -2.164 to -1.000, for 10 mg (n = 1079) and -1.668%, 95% CI -2.260 to -1.077, for 25 mg (n = 1070)] and FPG [SMD -0.865 mmol/L, 95 % CI -1.309 to -0.420, for 10 mg (n = 854) and -0.996 mmol/L, 95% CI -1.456 to -0.536, for 25 mg (n = 854)] were also observed in empagliflozin add-on therapy trials. Reductions in blood pressure and body weight were also seen in both monotherapy and add-on therapy. Empagliflozin was associated with increased risk of hypoglycemia, genital and urinary tract infections (OR 1.043, 2.814, 1.119 respectively). CONCLUSION: This meta-analysis shows empagliflozin is safe and effective for the treatment of T2DM along with existing diabetes pharmacotherapy.

Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials.

BACKGROUND: Currently available antihyperglycemic agents (AHAs), despite being effective, do not provide adequate glycemic control in some cases and are associated with side effects. A sodium glucose co-transporter 2 inhibitor, canagliflozin, is a newer AHA, which acts by decreasing the reabsorption of filtered glucose thereby elevating the urinary glucose excretion in diabetics. AREAS COVERED: This systematic review was completed to assess the clinical effectiveness and safety of canagliflozin in T2DM. A literature search in PubMed, MEDLINE, Cochrane and ClinicalTrials.gov was conducted for randomized clinical trials of canagliflozin as an AHA by applying predetermined inclusion and exclusion criteria. Total 13 studies were included in the systematic review. The main outcomes assessed were change in HbA1c and fasting plasma glucose. EXPERT OPINION: Canagliflozin monotherapy or combination therapy has the potential to decrease inadequately controlled hyperglycemia in T2DM. It acts by a novel insulin independent mechanism which complements the action of the existing AHA and improves glycemic control and decreases the body weight. Safety profile of canagliflozin indicates lower number of hypoglycemic episodes. Some manageable adverse events include genital mycotic infections, urinary tract infections, osmotic diuresis-related events etc. These findings affirm the utility of canagliflozin in T2DM; however, data on long-term safety and efficacy are needed.