Isoquinoline Ring System Research Articles

Naturally Available Nitrogen-Containing Fused Heterocyclics as Prospective Lead Molecules in Medicinal Chemistry

Heterocyclic compounds constitute one of the largest and most versatile families of organic compounds. There are many heterocyclic compounds that are being isolated from natural sources and day by day the number is increasing rapidly due to their enormous utility. Nitrogen containing heterocyclic compounds have a prominent role in medicinal chemistry, biochemistry and other streams of science. In this review, we have covered most of the biologically active nitrogen containing heterocyclic compounds obtained from the natural sources including indole, carbazole, quinoline, isoquinoline and benzothiazole ring system. These isolated nitrogen containing heterocyclic compounds render wide spectrum of biological activities including antifungal, anti-inflammatory, antibacterial, antioxidants, anticonvulsant, anti-allergic, herbicidal and anticancer activities.

Crystal structure and Hirshfeld surface analysis of 3-amino-1-oxo-2,6,8-triphenyl-1,2,7,8-tetra-hydro-iso-quinoline-4-carbo-nitrile.

In the title compound, C28H21N3O, the 1,2-di-hydro-pyridine ring of the 1,2,7,8-tetra-hydro-iso-quinoline ring system is planar as expected, while the cyclo-hexa-1,3-diene ring has a twist-boat conformation, with Cremer-Pople parameters Q T = 0.367 (2) A, θ = 117.3 (3)° and φ = 327.3 (4)°. The dihedral angles between the best planes through the iso-quinoline ring system and the three phenyl rings are 81.69 (12), 82.45 (11) and 47.36 (10)°. In the crystal, mol-ecules are linked via N-H⋯O and C-H⋯N hydrogen bonds, forming a three-dimensional network. Furthermore, the crystal packing is dominated by C-H⋯π bonds with a strong inter-action involving the phenyl H atoms. The role of the inter-molecular inter-actions in the crystal packing was clarified using Hirshfeld surface analysis, and two-dimensional fingerprint plots indicate that the most important contributions to the crystal packing are from H⋯H (46.0%), C⋯H/H⋯C (35.1%) and N⋯H/H⋯N (10.5%) contacts.

2H-Bis-1,2,3-triazolo-isoquinoline: Design, Synthesis, and Photophysical Study.

An efficient three-step synthesis of a new heterocyclic system is described wherein the 2H-bis([1,2,3]triazolo)[5,1-a:4',5'-c]isoquinoline ring system is elaborated using a simple synthetic strategy. The approach permits the preparation of target compounds in high yields using readily available arylhydrazines and o-alkynylbenzaldehydes as starting materials. The photophysical properties of the prepared heterocycles were studied to demonstrate that the prepared compounds are attractive blue-emitting fluorophores, exhibiting quantum yields up to 98% and Stokes shifts up to 67 nm. A strong effect of the steric hindrance on the absorption and emission spectra was revealed.

An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors.

Allosteric HIV-1 integrase inhibitors (ALLINIs) are a new class of potential antiretroviral therapies with a unique mechanism of action and drug resistance profile. To further extend this class of inhibitors via a scaffold hopping approach, we have synthesized a series of analogues possessing an isoquinoline ring system. Lead compound 6l binds in the v-shaped pocket at the IN dimer interface and is highly selective for promoting higher-order multimerization of inactive IN over inhibiting IN-LEDGF/p75 binding. Importantly, 6l potently inhibited HIV-1NL4-3 (A128T IN), which confers marked resistance to archetypal quinoline-based ALLINIs. Thermal degradation studies indicated that at elevated temperatures the acetic acid side chain of specific isoquinoline derivatives undergo decarboxylation reactions. This reactivity has implications for the synthesis of various ALLINI analogues.

Crystal structure and Hirshfeld surface analysis of 4'-(2-chloro-phen-yl)-1'-methyl-3''-phenyl-7'',8''-di-hydro-5''H-di-spiro-[indoline-3,2'-pyrrolidine-3',6''-iso-quinoline]-2,5''-dione.

In the title di-spiro compound, C32H26ClN3O2, the cyclo-hexa-none ring of the iso-quinoline unit has a distorted envelope conformation, with the methyl-ene C atom adjacent to the spiro C atom as the flap. The central 1-methyl-pyrrolidine ring has an envelope conformation with the N atom as the flap. The mean planes of the indolin-2-one ring system, the chloro-benzene ring and the iso-quinoline ring system are inclined to the mean plane of the central 1-methyl-pyrrolidine ring by 87.95 (11), 71.01 (12) and 88.81 (10)°, respectively. There are two short C-H⋯O intra-molecular contacts present. In the crystal, mol-ecules are linked via C-H⋯ O hydrogen bonds, forming chains along the a-axis direction. The NH H atom is involved in a weak N-H⋯O hydrogen bond with the same carbonyl O atom. There are no further significant inter-molecular contacts present. The largest contribution to the overall Hirshfeld surface of 52.3% is due to H-H contacts.

NRPS-Derived Isoquinolines and Lipopetides Mediate Antagonism between Plant Pathogenic Fungi and Bacteria.

Bacterial-fungal interactions are presumed to be mediated chiefly by small-molecule signals; however, little is known about the signaling networks that regulate antagonistic relationships between pathogens. Here, we show that the ralstonins, lipopeptides produced by the plant pathogenic bacteria Ralstonia solanacearum, interfere with germination of the plant-pathogenic fungus Aspergillus flavus by down-regulating expression of a cryptic biosynthetic gene cluster (BGC), named imq. Comparative metabolomic analysis of overexpression strains of the transcription factor ImqK revealed imq-dependent production of a family of tripeptide-derived alkaloids, the imizoquins. These alkaloids are produced via a nonribosomal peptide synthetase- (NRPS-)derived tripeptide and contain an unprecedented tricyclic imidazo[2,1-a]isoquinoline ring system. We show that the imizoquins serve a protective role against oxidative stress that is essential for normal A. flavus germination. Supplementation of purified imizoquins restored wildtype germination to a ΔimqK A. flavus strain and protected the fungus from ROS damage. Whereas the bacterial ralstonins retarded A. flavus germination and suppressed expression of the imq cluster, the fungal imizoquins in turn suppressed growth of R. solanacearum. We suggest such reciprocal small-molecule-mediated antagonism is a common feature in microbial encounters affecting pathogenicity and survival of the involved species.

Crystal structure of (3S*,4R*)-4-fluoro-3-(4-meth-oxy-phen-yl)-1-oxo-2-phenyl-1,2,3,4-tetra-hydro-iso-quinoline-4-carb-oxy-lic acid.

The title compound, C23H18FNO4, crystallized as a racemate. It exhibits a cis conformation with respect to the F atom and the methine H atom. The piperidine ring has a screw-boat conformation. The meth-oxy-phenyl ring and the phenyl ring are inclined to the mean plane of the iso-quinoline ring system by 89.85 (4) and 46.62 (5)°, respectively, and by 78.15 (5)° to one another. In the crystal, mol-ecules are linked by an O-H⋯O hydrogen bond forming chains propagating along the a-axis direction. The chains are linked by C-H⋯F hydrogen bonds, forming layers lying parallel to the ab plane.

σ N-C Bond Difunctionalization in Bridged Twisted Amides: Sew-and-Cut Activation Approach to Functionalized Isoquinolines.

A rare example of highly selective σ N-C bond difunctionalization in bridged twisted lactams through N-C cleavage has been achieved. In combination with the intramolecular Heck cyclization, this method affords a two-step bond reorganization event ("sew-and-cut") to access functionalized isoquinoline ring systems directly with high atom economy. C-H bond functionalizations directed by a weakly coordinating bridged amide bond increase scaffold diversity. Preliminary mechanistic studies on the effect of amide distortion and the role of electrophile in this unusual σ N-C amide difunctionalization are described.

7-Acetyl-8-(4-chlorophenyl)-3-ethylsulfanyl-6-hydroxy-1,6-dimethyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile

In the title compound, C22H23ClN2O2S, the chlorophenyl ring is inclined to the pyridine ring of the isoquinoline ring system by 79.78 (4)°. The cyclohexane ring adopts a flattened boat conformation. In the crystal, dimers form through complementary sets of inversion-related O—H...O and C—H...O hydrogen bonds. These are connected into zigzag chains along the c-axis direction by pairwise C—H...N interactions that also form inversion dimers.

Advances in the Preparation of Fluorinated Isoquinolines: A Decade of Progress

Heterocyclic molecules incorporating fluorinated isoquinoline components are found in many medicinally and agriculturally important bioactive products as well as industrially impactful materials. Within the past decade, a variety of isoquinolinic ring assembly techniques has enabled the introduction of diverse fluorine-containing functionalities which can enhance potential bioactivity and industrial utility. This review examines recent noncatalyzed and transition metal catalyzed synthetic approaches to the assembly of isoquinoline derivatives that are ring-fluorinated and/or result in the incorporation of fluorine-containing functional groups. Specifically, efficient synthetic methods and regioselectivity in the incorporation of functional groups into isoquinoline ring systems are examined.

Practical synthesis and cytotoxic evaluation of the pyrazino[1,2-b]-isoquinoline ring system.

A practical three-step protocol for the synthesis of pyrazino[1,2-b]isoquinolines is reported. This approach includes a one-pot parallel cyclization/cyclization parallel process followed by a non-common 6-endo Heck cyclization that transformed previously constructed Ugi adducts into diversely decorated tricyclic systems. Compounds bearing a t-butyl or 2,6-dimethylphenyl substituent showed significant cytotoxic activity. The most active analogue (6p) showed significant activity against HCT-15 and K562 (IC50 = 41.8 ± 3.3 and 57.7 ± 2.1 μM, respectively) with no cytotoxicity against human gingival fibroblasts.

Synthesis of Isoquinolines Derivatives from o-Alkynyl Aldehydes

The isoquinoline and dihydroisoquinoline ring systems are found as the core nucleus in a wide variety of natural products and pharmaceutical agents with good biologically activity. Isoquinoline, benzoxazine-fused isoquinlines and pyrazo- lo(5,1-a)isoquinolines are prepared from o-alkynyl aldehydes and nitrogen-containing compounds via tandem reactions cata- lyzed by CuI or AgNO3. The reactions have some advantages, such as mild reaction conditions, simple operation and easily available catalysts. Keywords isoquinoline; benzoxazine-fused isoquinlines; pyrazolo(5,1-a)isoquinolines; o-alkynyl aldehydes; tandem reac- tion

An efficient synthesis of substituted spiro[isoxazolopyrroloisoquinolines] via diastereoselective N-acyliminium ion cyclization

A simple and efficient strategy is reported for the synthesis of spiro-fused pyrrolo[2,1-a]isoquinoline ring systems. The spiro[isoxazolopyrroloisoquinolines] are readily prepared via diastereoselective N-acyliminium ion cyclization of 6-hydroxy-7-(2-arylethyl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-8-ones derived from the corresponding spirocyclic dihydroisoxazoles.

An efficient synthesis of substituted isoxazolopyrroloisoquinolines via diastereoselective N-acyliminium ion cyclization

A simple and efficient strategy was developed for the synthesis of fused pyrrolo[2,1-a]isoquinoline ring systems. The 5- and 6-substituted isoxazolopyrroloisoquinolines were readily prepared via diastereoselective N-acyliminium ion cyclization of 5-(1-R(or 2-R)-substituted-2-phenylethyl)-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]isoxazol-4-ones derived from the corresponding bicyclic dihydroisoxazoles.

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.

Superacid‐Promoted Cyclodehydration Leading to the Imidazo[2,1‐a]isoquinoline Ring System

AbstractA series of heterocycle‐substituted acetophenones were prepared and reacted with the Brønsted superacid CF3SO3H (triflic acid=trifluoromethanesulfonic acid). Cyclodehydration provided aryl‐substituted imidazo[2,1‐a]isoquinolines and related products (28–85%, seven examples). A mechanism is proposed involving dicationic intermediates.

Synthesis of Functional Heterocycles <i>via</i> Tandem Reaction

Tandem reactions for efficient construction of nitrogen-containing heterocycles were developed. One-pot platinum(II)-catalyzed synthesis of indoles and isoquinolines has been achieved via isocyanates, which were derived from a Hofmann-type rearrangement of 2-alkynylbenzamides and 2-alkynylbenzylamides using a hypervalent iodine reagent. As an extension of this approach, trans-2,3-dihydro-4-quinolones were synthesized via acid-catalyzed intermolecular [2+2]-cycloaddition of aldehydes and carbamates, which were formed from nucleophilic addition of alcohols to isocyanate intermediates. Direct, efficient syntheses of the benzimidazo[2,1-a]isoquinoline ring system have been achieved with 2-bromoarylaldehydes, terminal alkynes, and 1,2-phenylenediamines by a microwave-accelerated tandem process in which a Sonogashira coupling, 5-endo cyclization, oxidative aromatization, and 6-endo cyclization can be performed in a single synthetic operation.

10′-Chloro-3′,4′-dihydro-2′H-spiro[cyclopropane-1,7′(6′H)-pyrimido[2,1-a]isoquinolin]-6′-one

In the title compound, C14H13ClN2O, the fused hydro­pyrimidine ring adopts an envelope conformation with one of the methyl­ene C atoms at the flap. The three-membered ring is approximately perpendicular to the attached isoquinoline ring system, with a dihedral angle of 89.44 (11)°. In the crystal, mol­ecules are linked by a weak C—H⋯π inter­action, forming a helical chain along the c axis.

Methyl 2,2'-dimethyl-4'-[2-(methyl-sulfan-yl)eth-yl]-1,3-dioxo-2,3-dihydro-1H,4'H-spiro-[isoquinoline-4,5'-oxazole]-4'-carboxyl-ate.

In the isoquinoline ring system of the title mol­ecule, C18H20N2O5S, the fused N-heterocyclic ring is distorted towards a half-boat conformation. The methyl formate moiety is disordered over two sets of sites with refined occupancies of 0.882 (5) and 0.118 (5). In the crystal, mol­ecules are linked via weak inter­molecular C—H⋯O hydrogen bonds into one-dimensional chains along [010].

Methyl 2-acetamido-2-(4-hydroxy-2-methyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylpentanoate

In the isoquinoline ring system of the title mol­ecule, C19H24N2O6, the N-heterocyclic ring is in a half-boat conformation. The mol­ecular structure is stabilized by an intra­molecular O—H⋯O hydrogen bond, which generates an S(7) ring motif. In the crystal, mol­ecules are linked via inter­molecular bifurcated N—H⋯(O,O) and weak C—H⋯O hydrogen bonds into a three-dimensional network.