Isoquinoline Moiety Research Articles

Fragment-based virtual screening identifies novel leads against Plasmepsin IX (PlmIX) of Plasmodium falciparum: Homology modeling, molecular docking, and simulation approaches

Despite continuous efforts to develop safer and efficient medications, malaria remains a major threat posing great challenges for new drug discovery. The emerging drug resistance, increased toxicities, and impoverished pharmacokinetic profiles exhibited by conventional drugs have hindered the search for new entities. Plasmepsins, a group of Plasmodium-specific, aspartic acid protease enzymes, are involved in many key aspects of parasite biology, and this makes them interesting targets for antimalarial chemotherapy. Among different isoforms, PlmIX serves as an unexplored antimalarial drug target that plays a crucial role along with PlmV and X in the parasite’s survival by digesting hemoglobin in the host’s erythrocytes. In this study, fragment-based virtual screening was performed by modeling the three-dimensional structure of PlmIX and predicting its ligand-binding pocket by using the Sitemap tool. Screening identified the fragments with the XP docking score ≤ −3 kcal/mol from the OTAVA General Fragment Library (≈16,397 fragments), and the selected fragments were chosen for ligand breeding. The resulting ligands (≈69,858 ligands) were subsequently subjected to filtering based on the QikProp properties along with carcinogenicity testing performed using CarcinoPred-EL and then docked in the SP (≈14,078 ligands) as well as XP mode (≈3,104 ligands), and compared with that of control ligands 49C and I0L. The top-ranked ligands were taken further for the calculation of the free energy of binding using Prime MM–GBSA. Overall, a total of six complexes were taken further for MD simulation studies performed at 100 ns to attain a better understanding of the binding mechanisms, and compounds 3 and 4 were found to be the most efficient ones in silico. The analysis of compound 3 revealed that the carbonyl group present in position 1 on the isoindoline moiety (Arg554) was responsible for inhibitory activity against PlmIX. However, the analysis of compound 4 revealed that the amide linkage sandwiched between the phenyl ring and isoquinoline moiety (Lys555 and Ser226) as well as carbonyl oxygen of the carbamoyl group present at position 2 of the pyrazole ring (Gln222) were responsible for PlmIX inhibitory activity, owing to their crucial interactions with key amino acid residues.

Control of the geometry and anisotropy driven by the combination of steric and anion coordination effects in CoII complexes with N6-tripodal ligands: the impact of the size of the ligand on the magnetization relaxation time.

Four mononuclear CoII complexes of formula [Co(L)(SCN)2(CH3OH)0.5(H2O)0.5]·1.5H2O·0.75CH3OH (1), [Co(L1)Cl2]·H2O·2CH3CN (2), [Co(L1)(SCN)2]·1.5H2O·CH3OH (3) and [Co(L1)]ClO4·2CH3OH (4) were prepared from the N6-tripodal Schiff base ligands (S)P[N(Me)NC(H)2-Q]3 (L) and (S)P[N(Me)NC(H)1-ISOQ]3 (L1), where Q and ISOQ represent quinolyl and isoquinolyl moieties, respectively. In 1, the L ligand does not coordinate to the CoII ion in a tripodal manner but using a new N,N,S tridentate mode, which is due to the fact that the N6-tripodal coordination promotes a strong steric hindrance between the quinolyl moieties. However, L1 can coordinate to the CoII ions either in a tripodal manner using CoII salts with poorly coordinating anions to give 4 or in a bisbidentate fashion using CoII salt-containing medium to strongly coordinating anions to afford 2 and 3. In the case of L1, there is no steric hindrance between ISOQ moieties after coordination to the CoII ion. The CoII ion exhibits a distorted octahedral geometry for compounds 1-3, with the anions in cis positions for the former and in trans positions for the two latter compounds. Compound 4 shows an intermediate geometry between an octahedral and trigonal prism but closer to the latter one. DC magnetic properties, HFEPR and FIRMS measurements and ab initio calculations demonstrate that distorted octahedral complexes 1-3 exhibit easy-plane magnetic anisotropy (D > 0), whereas compound 4 shows large easy-axis magnetic anisotropy (D < 0). Comparative analysis of the magneto-structural data underlines the important role that is played not only by the coordination geometry but also the electronic effects in determining the anisotropy of the CoII ions. Compounds 2-3 show a field-induced slow relaxation of magnetization. Despite its large easy-axis magnetic anisotropy, compound 4 does not show significant slow relaxation (SMR) above 2 K under zero applied magnetic fields, but its magnetic dilution with ZnII triggers SMR at zero field. Finally, it is worth remarking that compounds 2-4 show smaller relaxation times than the analogous complexes with the tripodal ligand bearing in its arms pyridine instead of isoquinoline moieties, which is most likely due to the increase of the molecular size in the former one.

5,8-Quinolinedione Attached to Quinone Derivatives: XRD Diffraction, Fourier Transform Infrared Spectra and Computational Analysis

Quinoline and isoquinoline moieties occur in many natural and synthetic compounds exhibiting high biological activity. The purpose of this study was to analyze the chemical structures of 5,8-quinolinedione and 5,8-isoquinoline derivatives using FT-IR spectroscopy supplemented with theoretical DFT calculations. Spectroscopic measurements were conducted using the attenuated total reflection (ATR) mode in the frequency range of 4000–400 cm−1. An analysis of FT-IR spectra was carried out, assigning the characteristic vibration frequencies of various functional groups to individual peaks. It was found that the experimental and calculated FT-IR spectra showed a good correlation for all the compounds under study. The most significant difference in the spectra occurred in the region of carbonyl bands. For compounds with the 5,8-quinolinedione moiety, two separated C=O vibration peaks were observed, while for compounds with the 5,8-isoquinolinedione moiety, the carbonyl vibrations created only one peak. This difference makes it possible to distinguish between the 5,8-quinolinedione and 5,8-isoquinolinedione derivatives.

Sterically attenuated electronic communication in cobalt complexes of meridional isoquinoline-derived ligands for applications in electrocatalysis.

The ability to synthetically tune the ligand frameworks of redox-active molecules is of critical importance to the economy of solar fuels because manipulating their redox properties can afford control over the operating potentials of sustained electrocatalytic or photoelectrocatalytic processes. The electronic and steric properties of 2,2':6',2″-terpyridine (Terpy) ligand frameworks can be tuned by functional group substitution on ligand backbones, and these correlate strongly to their Hammett parameters. The synthesis of a new series of tridentate meridional ligands of 2,4,6-trisubstituted pyridines that engineers the ability to finely tune the redox potentials of cobalt complexes to more positive potentials than that of their Terpy analogs is achieved by aryl-functionalizing at the four-position and by including isoquinoline at the two- and six-positions of pyridine (Aryl-DiQ). Their cobalt complex syntheses, their electronic properties, and their catalytic activity for carbon dioxide (CO2) reduction are reported and compared to their Terpy analogs. The cobalt derivatives generally experience a positive shift in their redox features relative to the Terpy-based analogs, covering a complementary potential range. Although those evaluated fail to produce any quantifiable products for the reduction of CO2 and suffer from long-term instability, these results suggest possible alternate strategies for stabilizing these compounds during catalysis. We speculate that lower equilibrium association constants to the cobalt center are intrinsic to these ligands, which originate from a steric interaction between protons on the pyridine and isoquinoline moieties. Nevertheless, the new Aryl-DiQ ligand framework has been engineered to selectively tune homoleptic cobalt complexes' redox potentials.

Molecular Docking, ADMET Analysis and Molecular Dynamics (MD) Simulation to Identify Synthetic Isoquinolines as Potential Inhibitors of SARS-CoV-2 MPRO.

The rapidly widespread SARS-CoV-2 infection has affected millions worldwide, thus becoming a global health emergency. Although vaccines are already available, there are still new COVID-19 cases daily worldwide, mainly due to low immunization coverage and the advent of new strains. Therefore, there is an utmost need for the discovery of lead compounds to treat COVID-19. Considering the relevance of the SARS-CoV-2 MPRO in viral replication and the role of the isoquinoline moiety as a core part of several biologically relevant compounds, this study aimed to identify isoquinoline-based molecules as new drug-like compounds, aiming to develop an effective coronavirus inhibitor. 274 isoquinoline derivatives were submitted to molecular docking interactions with SARS-CoV-2 MPRO (PDB ID: 7L0D) and drug-likeness analysis. The five best-docked isoquinoline derivatives that did not violate any of Lipinski's or Veber's parameters were submitted to ADMET analysis and molecular dynamics (MD) simulations. The selected compounds exhibited docking scores similar to or better than chloroquine and other isoquinolines previously reported. The fact that the compounds interact with residues that are pivotal for the enzyme's catalytic activity, and show the potential to be orally administered makes them promising drugs for treating COVID-19. Ultimately, MD simulation was performed to verify ligand-protein complex stability during the simulation period.

Synthesis of a Blue-Emissive Azaborathia[9]helicene by Silicon-Boron Exchange from Unusual Atropisomeric Teraryls.

We report the concise synthesis and chir(optical) properties of an azaborathia[9]helicene consisting of two thienoazaborole motifs. The key intermediate, a highly congested teraryl with nearly parallel isoquinoline moieties, was generated as a mixture of atropisomers upon fusion of the central thiophene ring of the dithienothiophene moiety. These diastereomers were characterized by single crystal X-ray analysis revealing intriguing interactions in the solid state. Subsequent insertion of boron into the aromatic scaffold via silicon-boron exchange involving triisopropylsilyl groups fixed the helical geometry, thereby establishing a novel method for the preparation of azaboroles. The ligand exchange at boron in the final step afforded the blue emitter displaying a fluorescence quantum yield of 0.17 in CH2 Cl2 and excellent configurational stability. Detailed structural and theoretical investigation of unusual atropisomers and the helicene provide insights into their isomerization processes.

Synthesis of a Blue‐Emissive Azaborathia[9]helicene by Silicon‐Boron Exchange from Unusual Atropisomeric Teraryls

AbstractWe report the concise synthesis and chir(optical) properties of an azaborathia[9]helicene consisting of two thienoazaborole motifs. The key intermediate, a highly congested teraryl with nearly parallel isoquinoline moieties, was generated as a mixture of atropisomers upon fusion of the central thiophene ring of the dithienothiophene moiety. These diastereomers were characterized by single crystal X‐ray analysis revealing intriguing interactions in the solid state. Subsequent insertion of boron into the aromatic scaffold via silicon‐boron exchange involving triisopropylsilyl groups fixed the helical geometry, thereby establishing a novel method for the preparation of azaboroles. The ligand exchange at boron in the final step afforded the blue emitter displaying a fluorescence quantum yield of 0.17 in CH2Cl2 and excellent configurational stability. Detailed structural and theoretical investigation of unusual atropisomers and the helicene provide insights into their isomerization processes.

Newly Synthesized Arylazo Derivatives Induce Apoptosis and G2/M Cell Cycle Arrest With Molecular Docking Validation in Human Cancer Cell Lines.

We reported herein the synthesis of novel arylazo derivatives 3a-e incorporating isoquinoline moiety. A coupling reaction of 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile 1 with diazotized heterocyclic amines 2 in ethanol in the presence of sodium acetate to give arylazo derivatives 3a-e. Cytotoxic effect of five arylazo derivatives on breast carcinoma MCF7 and hepatocellular carcinoma HepG2 was carried out, followed by molecular and functional-based assays, to estimate the anticancer effect of these compounds. The fibroblast growth factor receptor (FGFR) and epithelial growth factor receptor (EGFR) were found to interact and bind with the compounds 3a and 3d through several hydrophobic and hydrogen bonds, which were validated by molecular docking. The two promising compounds 3a and 3d demonstrated various anticancer potential activities on tumorigenesis, cytotoxicity, and apoptotic effects, exhibited in the deregulation of the expression of different genes involved in apoptotic and anti-apoptotic mechanisms, cell cycle arrest at G2/M, and induction of apoptosis in both cell lines.

Jozibrevine D from Ancistrocladus ileboensis, the fifth alkaloid in a series of six possible atropo-diastereomeric naphthylisoquinoline dimers, showing antiparasitic and antileukemic activities

A new dimeric naphthylisoquinoline alkaloid, jozibrevine D (4e), was isolated from the Central-African liana Ancistrocladus ileboensis. It is a Dioncophyllaceae-type metabolite, being R-configured at C-3 and lacking an oxygen function at C-6 in both isoquinoline moieties. The two identical monomers of jozibrevine D are symmetrically linked via the sterically constrained 3′,3′'-positions of the naphthalene units so that the central biaryl linkage is rotationally hindered and the alkaloid is, thus, C2-symmetric. With the two outer biaryl bonds being chiral, too, 4e possesses three consecutive stereogenic axes. The absolute stereostructure of the new compound was assigned by 1D and 2D NMR, ruthenium-mediated oxidative degradation, and electronic circular dichroism (ECD) spectroscopy. Jozibrevine D (4e) is the fifth discovered isomer in a series of six possible natural atropo-diastereomeric dimers. It shows potent, and selective, antiprotozoal activity against P. falciparum (IC50 = 0.14 μM), and it also exhibits good cytotoxic activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells (IC50 = 11.47 μM) and their multidrug-resistant CEM/ADR5000 subline (IC50 = 16.61 μM).

Crystal structures of two new carbazole derivatives: ethyl 9-(benzenesulfonyl)-2-(4-fluoro-2-nitrophenyl)-6-methoxy-9H-carbazole-3-carboxylate and 12-(benzenesulfonyl)-12H-quinolino[4,3-b]carbazole

The title compounds, C28H21FN2O7S (I) and C25H16N2O2S (II), are carbazole derivatives with a benzenesulfonyl group attached to the carbazole moiety at the N atom on both molecules. A fluoro-substituted nitrophenyl ring system in I and a fused isoquinoline ring in II are attached to the respective carbazole moieties. In both compounds, the carbazole ring systems are essentially planar, with maximum deviations of 0.028 (2) and 0.026 (2) Å for carbon atoms in compounds I and II, respectively. The carbazole ring system is almost orthogonal to the benzene ring attached to sulfonyl group, with dihedral angles of 79.7 (2) in I and 88.2 (2)° in II, respectively. The mean planes of the carbazole ring systems make dihedral angles of 66.1 (2) and 1.3 (2)°, respectively, with the nitrophenyl ring in I and the planar isoquinoline moiety [maximum deviation of 0.009 (3) Å for a carbon atom in II, indicating that the ring system in II is essentially planar]. The benzenesulfonyl ring is almost normal to the isoquinoline ring, with a dihedral angle of 87.9 (2)° in II and the nitrophenyl ring forms a dihedral angle of 17.8 (2)° in I. In both compounds, intramolecular C—H...O hydrogen bonds generate S(6) ring motifs with the sulfone group O atoms. In crystals of compound I, the molecules are linked by C—H...O intermolecular weak hydrogen bonds, which generate C(7) and C(10) chains running parallel to [010] and [100], respectively.

Synthesis, reaction, antimicrobial, and docking study of new chalcones incorporating isoquinoline moiety

Reaction of isoquinoline 1 with hydrazonoyl chlorides 2A–E gave the corresponding triazoloisoquinolines 4A–E. The latter products 4A–E were reacted with 4-(piperidin-1-yl)benzaldehyde 5a and 4-morpholinobenzaldehyde 5b to afford the corresponding chalcones 6a,b. Some of chalcones 6 were reacted with hydrazine hydrate in refluxing ethanol to give the corresponding 8,9-dimethoxy-1-aryl-4,5-dihydro-1H-pyrazol-3-yl-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline derivatives 7A–C. Antimicrobial studies were performed using gram-negative bacteria (Escherichia coli) and (Klebsiella pneumonia), a gram-positive bacteria (Streptococcus mutans) and (Staphylococcus aureus), filamentous fungus (Asperagillus Nigar) and yeast (Candida albicans). Data revealed that chalcone 6Aa achieved the lowest MIC values (high efficient derivative) against the sensitive bacterial strain E. coli with MIC value 130 µg/ml. The most effective compound 6Aa, which demonstrated the highest binding affinity toward tested protein [thymidine phosphorylase enzyme, (PDB ID:4EAD)], was docked using MOE 2014.09 software.

The Stereoselective Total Synthesis of Axially Chiral Naphthylisoquinoline Alkaloids.

The naphthylisoquinoline (NIQ) alkaloids are a thrilling class of natural biaryls─structurally, biosynthetically, and pharmacologically. A common feature of these metabolites is the biaryl bond between their naphthalene and isoquinoline moieties, which in most cases is rotationally hindered, leading to the phenomenon of axial chirality. Depending on their individual structures, including the respective axial configurations, NIQs show promising bioactivities. Their total synthesis is a challenging but rewarding goal, with the stereocontrolled construction of the biaryl linkage as the key step.The position of the biaryl axis and its configuration determine the overall molecular shape and thus the choice of the best possible method for efficient asymmetric aryl-aryl bond formation. The axis in NIQs can cover a broad range of steric hindrance, from freely rotating to configurationally stable. For dioncophylline B (1) and dioncophylline F (2a/b), with only two ortho-substituents next to the axis, the synthesis is easy to accomplish by direct coupling of the intact naphthalene moiety with the isoquinoline unit, and no atropo-selectivity is required.Naphthylisoquinolines with a configurationally stable biaryl axis are the focus of the present Account. They are more difficult to synthesize because, in addition to the problem of decreased chemical yields with increasing steric hindrance at the axis, the synthesis needs to proceed stereoselectively. Within this class of NIQs, 5,8'-coupled representatives, such as korupensamine A (3a), have received considerable synthetic attention because the rotational barrier is high enough for the existence of atropisomerism without being too excessive, and they show potent bioactivities. Their synthesis, as systematically presented herein, thus occupies a central role in this report. For their aryl-aryl bond formation, both intra- and intermolecular approaches can be successfully applied. Axial stereoinformation is introduced by internal asymmetric induction from stereogenic elements already present in the isoquinoline or its precursors, from chiral auxiliary elements artificially introduced, or by external asymmetric induction using chiral catalysts.To overcome even higher steric hindrance, as in ancistrocladine (4a), innovative approaches were developed. A most successful strategy is the "lactone concept" developed by the Bringmann group, which allows the directed synthesis of any desired atropisomer in high chemical and optical yields, thus permitting the atropo-divergent preparation of the two isomers from a single joint precursor. In this approach, the two formal tasks of stereoselective biaryl synthesis, which are usually done simultaneously─the C-C linkage and the asymmetric induction─are achieved consecutively. The coupling step is performed intramolecularly after prefixation of the coupling partners by an ester bridge. The resulting biaryl lactone already possesses the biaryl axis but is still configurationally unstable; it can then, with internal or external asymmetric induction, be cleaved atropo-divergently with high stereoselectivities. Besides its unique concept, the procedure excels by its broad applicability; among all presented methods, it has been used for the synthesis of the largest number of NIQs, more than 20 representatives, including those with the highest steric hindrance.This Account gives comprehensive insight into the plethora of conceptual approaches for the efficient formation of the hindered biaryl bond of NIQs.

Aryl/Heteroaryl Substituted Boron-Difluoride Complexes Bearing 2-(Isoquinol-1-yl)pyrrole Ligands Exhibiting High Luminescence Efficiency with a Large Stokes Shift.

A series of 2-(isoquinol-1-yl)pyrrole-boron complexes possessing (hetero)aryl substituents on the pyrrole and/or isoquinoline moiety were prepared. These compounds exhibited the fluorescence emission character in both solution and solid state. In most cases, the large Stokes shift and high fluorescence quantum yield in the solution were compatible. Furthermore, the structural diversity allowed the precise tuning of emitting colors from light blue to red with strong emission intensity. The present paper describes their comprehensive optical characteristics dependent on the type and position of the substituted aryl groups by the experimental and computational studies.

Role of kinetic stabilization in the inclusion of the pharmaceutically important chelerythrine and nitidine alkaloids in cucurbit[7]uril

The inclusion of chelerythrine and nitidine quaternary benzo[c]phenanthridine plant alkaloids in cucurbit[7]uril (CB7) was studied by stopped-flow method, isothermal calorimetry, spectrophotometric and fluorescence titrations in aqueous solution at pH 4. The molecular structure of the guests differed only in the position of a methoxy group linked to the isoquinoline moiety. Despite the minor alteration in the substitution pattern, fundamentally dissimilar kinetic and thermodynamic characteristics were found for the two alkaloids. Nitidine encapsulation in CB7 was kinetically stabilized because the activation enthalpy significantly exceeded the exothermicity of the binding. In contrast, chelerytrine-CB7 complex formation had slightly lower energy barrier and the ∼ 20 kJ mol−1 larger enthalpy gain significantly contributed to the driving force of association. The rates of exit from CB7 differed to a small extent for the two alkaloids because the effect of the lower activation enthalpy of nitidine egression was almost compensated by the unfavourable activation entropy of the process.

Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome.

A new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant Staphylococcus aureus (S. aureus) strains is presented. HSN584 and HSN739, representative compounds in this class, reduce methicillin-resistant S. aureus (MRSA) load in macrophages, whilst vancomycin, a drug of choice for MRSA infections, was unable to clear intracellular MRSA. Additionally, both HSN584 and HSN739 exhibited a low propensity to develop resistance. We utilized comparative global proteomics and macromolecule biosynthesis assays to gain insight into the alkynyl isoquinoline mechanism of action. Our preliminary data show that HSN584 perturb S. aureus cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety is a new scaffold for the development of potent antibacterial agents against fatal multidrug-resistant Gram-positive bacteria.

Metal‐free and One‐pot for the Synthesis of Indolo[2,1‐a]isoquinoline Aldehyde via a Free Radical Cascade Pathway followed by Direct Hydrolyzation

AbstractAs one of the most versatile intermediate group in synthetic chemistry, the introduction of an aldehyde group into a specific moiety is important for the transformation of molecular structures. Herein, we provided a metal‐free, regioselective and one‐pot formylation of the indolo[2,1‐a]isoquinoline moiety. This strategy features an oxidative coupling process using commercially available 1,3‐dioxolane as a formylated reagent followed by direct hydrolyzation without a separation process. This reaction can be carried out under common reaction conditions and displays broad functional group tolerance.

Crystal structure and Hirshfeld analysis of diethyl (2E,2'E)-3,3'-[1-(8-phenyl-isoquinolin-1-yl)-1H-indole-2,7-di-yl]diacrylate.

The mol-ecule of title compound, C33H28N2O4, comprises an indole unit (A), an iso-quinoline moiety (B) and a benzene ring (C). The dihedral angles between these groups are A/B = 57.47 (1), A/C = 18.48 (1) and B/C = 57.97 (1) °. The ethyl acrylate group at the 2-position is nearly co-planar with the indole unit [3.81 (2)°], while that at the 7-position is distinctly non-coplanar [52.64 (1)°]. Intra-molecular π-π inter-actions between the indole unit and benzene ring help to establish the clip-shaped conformation of the mol-ecule. In the crystal, the mol-ecules are assembled into two-dimensional layers via C-H⋯O hydrogen bonds, π-π and C-H⋯π inter-actions. Hirshfeld surface analysis illustrates that the greatest contributions are from H⋯H (63.2%), C⋯H/H⋯C (15.4%) and O⋯H/H⋯O (14.8%) contacts. The terminal C2H5 group of one of the ethyl acrylate side chains is disordered over two positions of equal occupancy.

Synthesis and Cytotoxicity of Novel Indoloquinolines and Benzonaphthyridines from 4‐Chloro‐2,8‐dimethylquinoline and Variety of Hetero Amines

AbstractThe synthesis of hetero substituted indoloquinolines and thiophene substituted benzonaphthyridienes from two heterocycles tethered by nitrogen or sulfur intermediates. Further it was cyclized using Pd(OAc)2 catalyst to yield products, i. e., various heteroindolo quinolines and polyphosphoric acid (PPA) mediated thiophene substituted naphthyridines. All the potential intermediates and their respective final products were screened for anticancer activity against HeLa and K562 cancer cells, and it showed good cytotoxicity against HeLa and K562 cells compared standard Adriamycin (ADR) drugs. Among the newly synthesized compounds, compounds 3 a, 3 b, 4 b and 5 a displayed stronger cytotoxic activity against both HeLa and K562 cells compared standard Adriamycin (ADR) drug. This might be due to the presence of benzothiazole and isoquinoline moieties, which enhanced the cytotoxic activity. Subsequently, compounds 3 c, 3 d, 4 a, 5 b and 7 also showed better cytotoxic activity with IC50 values &lt;19 μM against HeLa and K562 cells, which was due to the presence of quinoline and thiophene moieties, which enhanced the cytotoxic activity.

Multiple Myeloma Inhibitory Activity of Plant Natural Products.

Simple SummaryMultiple myeloma is the second most common hematological cancer and is still incurable. Although enhanced understanding of the disease background and the development of novel therapeutics during the last decade resulted in a significant increase of overall survival time, almost all patients relapse and finally succumb to their disease. Therefore, novel medications are urgently needed. Nature-derived compounds still account for the majority of new therapeutics and especially for the treatment of cancer often serve as lead compounds in drug development. The present review summarizes the data on plant natural products with in vitro and in vivo activity against multiple myeloma until the end of 2020, focusing on their structure–activity relationship as well as the investigated pathways and involved molecules.A literature search on plant natural products with antimyeloma activity until the end of 2020 resulted in 92 compounds with effects on at least one human myeloma cell line. Compounds were divided in different compound classes and both their structure–activity-relationships as well as eventual correlations with the pathways described for Multiple Myeloma were discussed. Each of the major compound classes in this review (alkaloids, phenolics, terpenes) revealed interesting candidates, such as dioncophyllines, a group of naphtylisoquinoline alkaloids, which showed pronounced and selective induction of apoptosis when substituted in position 7 of the isoquinoline moiety. Interestingly, out of the phenolic compound class, two of the most noteworthy constituents belong to the relatively small subclass of xanthones, rendering this group a good starting point for possible further drug development. The class of terpenoids also provides noteworthy constituents, such as the highly oxygenated diterpenoid oridonin, which exhibited antiproliferative effects equal to those of bortezomib on RPMI8226 cells. Moreover, triterpenoids containing a lactone ring and/or quinone-like substructures, e.g., bruceantin, whitaferin A, withanolide F, celastrol, and pristimerin, displayed remarkable activity, with the latter two compounds acting as inhibitors of both NF-κB and proteasome chymotrypsin-like activity.

Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer's Disease Potential.

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 μM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer’s disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent para-phenylene DHPPIQ Schiff base 14 exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with Ki in the low micromolar range (4.69 μM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC50) = 12 μM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced β-amyloid (Aβ)1–40 aggregation (IC50 = 13 μM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9.