RESUMO
This article describes an enantioselective strategy for the synthesis of the kainoid component, (+)-allokainic acid using an organocatalytic approach. A cross-aldol reaction catalyzed by diphenylprolinol yielded a highly functionalized γ-lactam with excellent enantio- and diastereoselectivity, and the resulting hydroxy pyrrolidone was then utilized to synthesize Ganem's intermediate of (+)-allokainic acid. Krapcho decarboxylation and Wittig olefination were pivotal transformations towards the final trans-substituted Ganem's intermediate.
RESUMO
A new series of syn-functionalised chiral hydroxy pyrrolidines and pyrrolidones containing α,ß-contiguous stereocenters were synthesized via a diphenylprolinol-catalysed asymmetric cross aldol reaction. The synthesized compounds were characterised and evaluated for their α-glucosidase inhibitory potential. The hydroxy pyrrolidine series (9a-9i) was found to be selectively more potent against the α-glucosidase enzyme as compared to the pyrrolidone series (10a-10i). Pyrrolidine 9b was the most efficacious analogue with an IC50 of 48.31 µM. Compounds 9c, 9d, & 9f were also found to be more potent than the standard drugs acarbose, miglitol and deoxynojirimycin. Furthermore, these compounds were investigated by computational studies using the GLIDE docking module of the Schrödinger suite 2021-4 in which 9b and 9c showed more promising results than the standard drugs acarbose, miglitol, and deoxynojirimycin.
Assuntos
Inibidores de Glicosídeo Hidrolases , alfa-Glucosidases , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Acarbose , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Pirrolidinas/farmacologia , Pirrolidinonas/farmacologia , Estrutura MolecularRESUMO
A domino condensation-cyclization method is developed to synthesize indolizidine alkaloids using a P4O10/TfOH reagent system without the employment of either a catalyst or solvent. The use of a few aliphatic and aromatic dicarboxylic acids is shown along with various primary amines. This method is suitable for synthesizing pyrrolo[2,1-a]isoquinolines, pyrido[2,1-a]isoquinolines, and isoindolo[1,2-a]isoquinolinones in excellent yields. When phthalic acid is used, a workup with either NaBH4 or a saturated NaHCO3 solution provided 12b-H or 12b-OH isoindolo[1,2-a]isoquinolinones, respectively.
RESUMO
Secondary metabolites isolated from bioactive extracts of natural sources iteratively pioneer the research in drug discovery. Modern medicine is often inspired by bioactive natural products or the bio-functional motifs embedded in them. One of such consequential bio-functional motifs is the thiolane unit. Thiolane-based bioactive organic compounds have manifested a plethora of astonishing biological activities such as anti-viral, anti-cancer, anti-platelet, α-glucosidase inhibition, anti-HIV, immunosuppressive and anti-microbial activities which renders them excellent candidates in drug discovery. Hence, to scale up the accessibility of thiolane-based therapeutics its chemical syntheses is essential and in addition; a sneak peek in its biosynthesis would give a perspective for developing biomimetic syntheses. This review highlights the development of important thiolane-based therapeutics such as (i) Nuphar sesquiterpene thioalkaloids (ii) Thiosugar sulphonium salts from Salacia sp. (iii) Albomycins (iv) Thiolane-based therapeutics from Allium sp. (v) 4'-thionucleosides summarizing various synthetic strategies, biosynthesis and biological activity studies, covering literature till 2021. We anticipate that this review will inspire chemists and biochemists to take up the challenges encountered in the synthesis and development of thiolane-based therapeutics.
Assuntos
Compostos de Sulfidrila/química , Alcaloides/síntese química , Alcaloides/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos , Bactérias/efeitos dos fármacos , Produtos Biológicos/síntese química , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Fungos/efeitos dos fármacos , Humanos , Sesquiterpenos/químicaRESUMO
A synthetic flavone derivative 2-(benzo[d][1,3]dioxol-5-yl)-4H-chromen-4-one (BDC) was synthesized by the one pot reaction method and assessed for α-glucosidase inhibitory activity. The BDC demonstrated dose dependent inhibition of α-glucosidase activity. A maximum inhibition (99.3⯱â¯0.26%) of α-glucosidase was observed at 27.6⯵M. The maximum α-glucosidase inhibitory activity depicted by BDC 27.6⯵M concentration was 22.4 fold over the maximum inhibition observed with acarbose (97.72⯱â¯0.59% at 669.57⯵M), a standard commercial anti-diabetic drug. In contrast to acarbose that depicted competitive type inhibition, kinetic studies of α-glucosidase inhibition by BDC demonstrated non-competitive inhibition with Km of 0.71â¯mM-1 and a Vmax of 0.028â¯mmol/min. In silico studies suggest allosteric interaction of BDC with α-glucosidase at a minimum binding energy (ΔG) of -8.64â¯kcal/mol and Ki of 465.3â¯nM, whereas, acarbose interacted at the active site of α-glucosidase with ΔG of -9.23â¯kcal/mol and Ki of 172â¯nM. Thus BDC significantly inhibited α-glucosidase in comparison to acarbose. Moreover, BDC has been endorsed for drug likeness by evaluating it as per Lipinski rule of five. Thus, BDC can be a lead compound for the management of type-2 diabetes mellitus.
Assuntos
Benzodioxóis/química , Benzopiranos/química , Flavonas/química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , alfa-Glucosidases/metabolismo , Benzodioxóis/metabolismo , Benzopiranos/metabolismo , Domínio Catalítico , Flavonas/metabolismo , Inibidores de Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/metabolismo , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , alfa-Glucosidases/químicaRESUMO
Grewia nervosa is a herbal plant used in traditional medicine for different purposes. Bioassay-guided chemical fractionation of G. nervosa roots resulted in an identification of two known and one new compound, namely microgrewiapine A, homomicrogrewiapine, and N-methylmicrocosamine, respectively. Their structures were determined using combination of LC/HR-MS, 1 H-NMR, and IR spectral analyses and followed by comparison with those reported in the literature. The problematic separation of these alkaloids on traditional column chromatography (Silica gel, Octadecyl silane, Sephadex) was resolved by using HPLC. Structurally similar compounds from the piperidine family have been characterized by using HR-MS analysis in combination with NMR data of crude samples. The major constituent i.e. N-methylmicrocosamine isolated from the butanol fraction of methanol root extract (MRE) was found to possess the dose dependent α-glucosidase inhibition activity with an IC50 value of 53.40 µm. Furthermore, N-methylmicrocosamine showed maximum α-glucosidase inhibition of 97.48 ± 0.7% at 107.5 µm, which is approximately 1.3 × 103 fold higher than the activity shown by acarbose (97.72% inhibition at 61.95 mm), a standard anti-diabetic drug available commercially. This work also reports the in vitro α-glucosidase inhibitory activity of the major alkaloids isolated from G. nervosa for the first time.
Assuntos
Alcaloides/química , Inibidores de Glicosídeo Hidrolases/química , Grewia/química , Piperidinas/química , Extratos Vegetais/química , alfa-Glucosidases/metabolismo , Alcaloides/isolamento & purificação , Alcaloides/metabolismo , Sítios de Ligação , Cromatografia Líquida de Alta Pressão , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/metabolismo , Grewia/metabolismo , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Simulação de Acoplamento Molecular , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Estrutura Terciária de Proteína , alfa-Glucosidases/químicaRESUMO
An I2/TBHP-mediated intramolecular dehydrogenative coupling reaction is developed for the synthesis of a library of medicinally important 5,11-dialkylindolo[3,2-c]quinoline salts and 5,7-dimethylindolo[2,3-c]quinoline salts. The annulation reaction is followed by aromatization to yield tetracycles in good yield. This protocol is also demonstrated for the synthesis of the naturally occurring isocryptolepine in salt form.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Indóis/química , Iodo/química , Quinolinas/síntese química , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Estrutura Molecular , Quinolinas/químicaRESUMO
A solvent free three component condensation reaction between an aldehyde, ethyl acetoacetate and urea catalyzed by graphite, a green catalyst is described for the synthesis of dihydropyrimidin-2(1H)-ones. This protocol is scalable and the catalyst is reusable. This method is also applied for the synthesis of dihydropyrimidin-2(1H)-thiones. α-Amylase, a key enzyme in carbohydrate metabolism is generally targeted for management of type 2 diabetes. The therapeutic potential of the dihydropyrimidinones and dihydropyrimidinthiones to inhibit α-amylase activity was evaluated by in vitro assay. Of the synthesized compounds 3,4-dihydropyrimidin-2(1H)-thione (1k) demonstrated highest inhibition of α-amylase activity.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Grafite/química , Hipoglicemiantes/farmacologia , Pirimidinas/farmacologia , Tionas/farmacologia , alfa-Amilases/antagonistas & inibidores , Catálise , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/química , alfa-Amilases/metabolismoRESUMO
Heterocyclic scaffolds represent the key structural subunits of many biologically active compounds. Over the last few years iodine-mediated reactions have been extensively studied due to their low cost and eco-friendliness. This Review covers advances in the field of iodine-mediated synthesis of heterocyclic compounds since 2006, especially with an emphasis on mechanisms of ring formation. In this article, syntheses of different heterocycles are classified based on the manipulation of functional groups.
Assuntos
Técnicas de Química Sintética/métodos , Compostos Heterocíclicos/síntese química , Iodo/química , Catálise , Compostos Heterocíclicos/químicaRESUMO
A synthesis of a series of novel 6H-indolo[2,3-b]quinolines with different substituents on the quinoline ring is described. The method involves reaction of indole-3-carboxyaldehyde with aryl amines in the presence of a catalytic amount of iodine in refluxing diphenyl ether to yield indolo[2,3-b]quinolines in one-pot. The present approach provides a new route for the synthesis of polycyclic structures related to an alkaloid cryptotackieine (neocryptolepine).
Assuntos
Alcaloides Indólicos/química , Indóis/química , Quinolinas/química , Catálise , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Espectrofotometria InfravermelhoRESUMO
The first stereoselective route providing access to both enantiomers of tedanalactam, a naturally occurring piperidone, has been developed. The stereogenic centers were generated by the use of Sharpless asymmetric dihydroxylation. Tandem oxidation-Wittig reaction and one-pot deprotection, lactamization, and oxirane ring formation are the other key elements.
Assuntos
Lactamas/química , Lactamas/síntese química , Piperidonas/química , Piperidonas/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Hidroxilação , EstereoisomerismoRESUMO
The first example of a tandem Wittig-intramolecular ene reaction approach and its application toward the synthesis of kainic acid is reported. The synthetic pathway involves conversion of prenyl bromide into phosphorane 3, followed by one-pot Wittig olefination and an ene reaction with glyoxalic acid to give the cis fused pyrrolidine skeleton of kainic acid.
Assuntos
Ácido Caínico/síntese química , Pirrolidinonas/síntese química , Pirrolidinonas/química , EstereoisomerismoRESUMO
Lipid peroxidation products 4-hydroxy-2(E)-nonenal (HNE) and 4-oxo-2(E)-nonenal (ONE) were conveniently synthesized using Wittig and Horner-Wardsworth-Emmons (HWE) reaction. Wittig or HWE reaction between an easily prepared phosphorane or phosphonate with glyoxal dimethyl acetal gave a protected 4-oxo-2(E)-nonenal. Hydrolysis gave 4-oxo-2(E)-nonenal, whereas reduction followed by hydrolysis gave 4-hydroxy-2(E)-nonenal.