ABSTRACT
The α- and ß-tubulins are the major polypeptide components of microtubules (MTs), which are attractive targets for anticancer drug development. Indole derivatives display a variety of biological activities including antitumor activity. In recent years, a great number of indole derivatives as tubulin polymerization inhibitors have sprung up, which encourages medicinal chemists to pursue promising inhibitors with improved antitumor activities, excellent physicochemical, pharmacokinetic and pharmacodynamic properties. In this review, the recent progress from 2010 to present in the development of indole derivatives as tubulin polymerization inhibitors was summarized and reviewed, which would provide useful clues and inspirations for further design of outstanding tubulin polymerization inhibitors.
ABSTRACT
Despite the fact that the introduction of a fluorine atom at the C-6 position has resulted in the evolution of fluoroquinolones, fluoroquinolone-induced cardiac toxicity has drawn considerable attention. In this context, desfluoroquinolone-based hybrids with involvement of C-7 aminopyrimidine functional group were designed and synthesized. The biological results showed majority of these hybrids still demonstrated potent anti-MRSA activity with MIC values between 0.38 and 1.5 µg/mL, despite the lack of the typical C-6 fluorine atom. Particularly, the most active B14 exhibited activities at submicromolar concentrations against a panel of MRSA strains including vancomycin-intermediate strains, levofloxacin-resistant isolates, and linezolid-resistant isolates, etc. As expected, it also displayed highly selective toxicity toward bacterial cells and low hERG inhibition. Further resistance development study indicated MRSA is unlikely to acquire resistance against B14. The docking study revealed that two hydrogen bonds were formed between the C-7 substituent and the surrounding DNA bases, which might contribute to overcome resistance by reducing the dependence on the magnesium-water bridge interactions with topoisomerase IV. These results indicate a promising strategy for developing new antibiotic quinolones to combat multidrug resistance and cardiotoxicity.
Subject(s)
Fluoroquinolones/chemical synthesis , Fluoroquinolones/therapeutic use , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Fluoroquinolones/pharmacology , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Molecular Structure , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07µM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules.
Subject(s)
Anti-HIV Agents/pharmacology , HIV-1/drug effects , Pyrimidines/pharmacology , Quinolones/pharmacology , Reverse Transcriptase Inhibitors/pharmacology , Anti-HIV Agents/chemical synthesis , Binding Sites , Cell Line , Drug Design , Granulocyte Precursor Cells/drug effects , Granulocyte Precursor Cells/pathology , Granulocyte Precursor Cells/virology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , HIV-1/growth & development , Humans , Models, Molecular , Molecular Docking Simulation , Pyrimidines/chemical synthesis , Quinolones/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Structure-Activity Relationship , Tetradecanoylphorbol Acetate/pharmacology , Virus Latency/drug effectsABSTRACT
A series of new DAPY-DPEs hybrids, combined the important pharmacophores of DAPYs and DPEs, has been synthesized and biologically evaluated for their anti-HIV activities against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Many promising candidates with potent inhibitory activity (wild-type) within the EC50 range from 0.16 to 0.013 µM were obtained. In particular, 3c, 3p, 3r and 3s displayed low nM level EC50 values (35, 13, 50 and 17 nM, respectively) and high selectivity (9342, 25131, 2890 and 11338, respectively), which were much more potent than NVP (EC50=0.31 µM, SI=48), 3TC (EC50=2.24 µM, SI>39), DDI (EC50=23.20 µM, SI>9) and DLV (EC50=0.65 µM, SI>67), and comparable to AZT (EC50=0.0071 µM, SI>13144) and EFV (EC50=0.0062 µM, SI>1014). The HIV-1 reverse transcriptase inhibitory assay confirmed that these DAPY-DPEs hybrids targeted HIV-1 RT. Molecular simulation was performed to investigate the potential binding mode of the newly synthesized compounds. And reasonable explanation for the activity results was discussed with docking method.
Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Pyrimidines/chemistry , Reverse Transcriptase Inhibitors/chemistry , Anti-HIV Agents/pharmacology , Binding Sites , Cell Line , Drug Design , Humans , Pyrimidines/pharmacology , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
2-Alkynylanilines are attractive starting materials in indole synthesis because of their ready availability. Herein, a one-pot stepwise procedure is reported for efficient construction of multisubstituted oxocino[4,3,2-cd]indoles from 2-alkynylanilines and 2-alkynylbenzaldoximes. The method comprises the oxidative dearomatization of 2-alkynylanilines, the silver-catalyzed [3+3] cycloaddition with 2-alkynylbenzaldoximes, and subsequent thermal radical skeletal rearrangement and aromatization.
ABSTRACT
The formation of carbon-carbon bonds through the functionalization of aromatic carbon-nitrogen bonds is a highly attractive synthetic strategy in the synthesis of aromatic molecules. In this paper, we report a novel aromatic carbon-nitrogen bond functionalization reaction by using a simple dearomatization strategy. Through this process para-substituted anilines serve as a potential aryl source in the construction of a range of functionalized aromatic molecules, such as quaternary carbon centers, α-keto esters, and aldehydes.
ABSTRACT
An efficient asymmetric synthesis of atorvastatin calcium has been achieved from commercially available diethyl 3-hydroxyglutarate through a novel approach that involves an organocatalytic enantioselective cyclic anhydride desymmetrization to establish C(3) stereogenicity and cyanide-free assembly of C7 amino type side chain via C5+C2 strategy as the key transformations.
Subject(s)
Calcium/chemistry , Cyanides/chemistry , Glutarates/chemistry , Heptanoic Acids/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Pyrroles/chemical synthesis , Anhydrides , Atorvastatin , Heptanoic Acids/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Pyrroles/chemistryABSTRACT
A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compounds 7f and 7g showed excellent activity against wild-type HIV-1 with low nanomolar EC50 values of 0.005 and 0.009 µM, respectively, which were comparable to or more potent than all the reference drugs zidovudine (AZT), lamivudine (3TC), nevirapine (NEV), efavirenz (EFV), delaviridine (DLV) and etravirine (ETV). In particular, 7g also displayed strong activity against the double mutant strain 103N + 181C with an EC50 value of 8.2 µM. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of CHX-DAPYs were also investigated.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Drug Design , HIV Reverse Transcriptase/antagonists & inhibitors , Pyrimidines/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Cell Survival/drug effects , Cells, Cultured , HIV-1/drug effects , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Nitriles , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/virology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured , Virus Replication/drug effectsABSTRACT
A series of CR2(OH)-diarylpyrimidine derivatives (CR2(OH)-DAPYs) featuring a hydrophobic group at CH(OH) linker between wing I and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. All the target compounds except for compound 3k displayed inhibitory activity against HIV-1 wild-type with EC50 values ranging from 7.21±1.99 to 0.067±0.006 µM. Among them, compound 3d showed the most potent anti-HIV-1 activity (EC50=0.067±0.006 µM, SI>592), which was approximately 2-fold more potent than the reference drugs nevirapine (NVP) and delaviridine (DLV) in the same assay. In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these new derivatives were also investigated.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Reverse Transcriptase Inhibitors/chemistry , Binding Sites , Cell Line , HIV Reverse Transcriptase/metabolism , Humans , Molecular Docking Simulation , Protein Structure, Tertiary , Pyrimidines/chemistry , Pyrimidines/metabolism , Reverse Transcriptase Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
The structural optimization of B14, an antibacterial agent we previously obtained, has led to the discovery of a new class of CH2-linked quinolone-aminopyrimidine hybrids with potent anti-MRSA activities. Surprisingly, the hybrids lacking a C-6 fluoro atom at the quinolone nucleus showed equal or even stronger anti-MRSA activities than their corresponding 6-fluoro counterparts, despite the well-established structure-activity relationships (SARs) indicating that the 6-fluoro substituent enhances the antibacterial activity in conventional fluoroquinolone antibiotics. Moreover, these new hybrids, albeit structurally related to conventional fluoroquinolones, showed no cross-resistance with fluoroquinolone drugs. The most active compound, 15m, exhibited excellent activities with a MIC value of 0.39 µg/mL against both fluoroquinolone-sensitive strain USA500 and -resistant MRSA isolate Mu50. Further resistance development studies indicated MRSA is unlikely to acquire resistance against 15m. Moreover, 15m displayed favorable in vivo half-life and safety profiles. These findings suggest a rationale for further evolution of quinolone antibiotics with a high barrier to resistance.
Subject(s)
Anti-Bacterial Agents , Fluoroquinolones , Methicillin-Resistant Staphylococcus aureus , Microbial Sensitivity Tests , Pyrimidines , Quinolones , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Methicillin-Resistant Staphylococcus aureus/drug effects , Structure-Activity Relationship , Pyrimidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Fluoroquinolones/pharmacology , Fluoroquinolones/chemistry , Fluoroquinolones/chemical synthesis , Quinolones/pharmacology , Quinolones/chemistry , Quinolones/chemical synthesis , Molecular Structure , Drug Resistance, Bacterial/drug effects , Dose-Response Relationship, Drug , Animals , HumansABSTRACT
A series of C6-rigid S-DABO analogs characterized by a substituted benzoyl group at C6 position of the pyrimidine ring has been synthesized and biological evaluation as NNRTIs against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 as well as HIV-2 strain ROD in MT-4 cell cultures. Most of the compounds exhibited moderate antiviral activities. Among them, compound 7q displayed the highest anti-HIV-1 activity with an EC50 value of 0.26µM and a selectivity index (SI) of 541. The preliminary structure-activity relationship (SAR) of these new S-DABOs was investigated, the target RT was confirmed and docking study was performed.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Pyrimidines/chemistry , Pyrimidinones/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Binding Sites , HIV Reverse Transcriptase/metabolism , Humans , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Pyrimidinones/chemistry , Pyrimidinones/metabolism , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
A series of new quinolone-3-carboxylic acids as HIV-1 integrase inhibitors featuring a fluorine atom at C-5 position were synthesized and evaluated for their antiviral activity in C8166 cell culture. These newly synthesized compounds showed anti-HIV activity against wild-type virus with an EC50 value ranging from 29.85 to 0.032 µΜ. The most active compound 4e exhibited activity against wild-type virus and the mutant virus A17 with an EC50 value of 0.032 and 0.082 µΜ, respectively. Preliminary structure-activity relationship of these 5-fluoroquinolone-3-carboxylic acids was also investigated.
Subject(s)
Anti-HIV Agents/pharmacology , Carboxylic Acids/pharmacology , Fluoroquinolones/pharmacology , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV/drug effects , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Cells, Cultured , Dose-Response Relationship, Drug , Fluoroquinolones/chemical synthesis , Fluoroquinolones/chemistry , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Cascade alkyl migration of 2-alkynylanilines via an aromaticity destruction and reconstruction process is reported. The first alkyl migration is triggered by generation of a dearomatized arenium species via oxidation and cyclization, and the second is driven by the force to restore the aromaticity of rearrangement products. The reaction gave rise to a range of multi-functionalized indoles.
ABSTRACT
A method for stereoselective construction of acyclic all-carbon tetrasubstituted alkenes through insertion of nitrile-substituted trimethylenemethane into the aryl C-N bond in anilines via an aromaticity destruction-reconstruction process is reported. The process involves dearomatization, azo-[3 + 2] TMM cycloaddition and aromatization-triggered rearrangement.
ABSTRACT
An anodic oxidative dearomatization reaction of 2-alkynylanilines was developed. The formed dearomatized compounds were used as versatile precursors in the synthesis of a variety of benzenoid ring multi-functionalized indoles through simple conversions.
Subject(s)
Indoles , Catalysis , Molecular Structure , Oxidation-ReductionABSTRACT
A process for the synthesis of C7-functionalized indoles using para-substituted 2-alkynylanilines as starting materials was reported. The process involves a dearomatization, an 1,2-addition by organic lithium or Grignard reagents, an aromatization-driven allylic rearrangement, and a cyclization. A variety of groups including alkyl, aryl, alkenyl, or alkynyl groups were selectively installed at the C7 site of indoles leading to the formation of 2,5,7-trisubstituted indoles.
ABSTRACT
A series of new quinolone-3-carboxylic acids featuring a hydroxyl group at C-5 position were synthesized and evaluated for their in vitro activity against HIV in C8166 cell culture. All the compounds showed anti-HIV-1 activity with low micromolar to submicromolar EC(50) values. The most active compound 2k exhibited activity against wild-type HIV-1 with an EC(50) value of 0.13 µΜ. Preliminary structure-activity relationship of the newly synthesized quinolone analogues was also investigated. Further docking study revealed that the anti-HIV activity of these compounds might involve a two-metal chelating mechanism.
Subject(s)
Anti-HIV Agents/chemical synthesis , Carboxylic Acids/chemical synthesis , HIV Infections/drug therapy , HIV-1/drug effects , Quinolones/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Carboxylic Acids/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , HIV Infections/pathology , HIV Seropositivity , Humans , Models, Molecular , Quinolones/chemistry , Quinolones/pharmacology , Quinolones/therapeutic use , Structure-Activity RelationshipABSTRACT
A series of 26 diarylpyrimidines, characterized by the hydroxymethyl linker between the left wing benzene ring and the central pyrimidine, were synthesized and evaluated for in vitro anti-HIV activity. Most of the compounds exhibited moderate to excellent activities against wild-type HIV-1. Among them, compound 10i, bearing a chlorine atom at the C-2 position of left benzene ring, was the best congener and showed potent activity against wild-type HIV-1 with an EC(50) value of 0.009 µM, along with moderate activities against the double RT mutant (K103N+Y181C) HIV-1(III(B)) and HIV-2(ROD) with an EC(50) value of 6.2 and 6.0 µM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated.
Subject(s)
Aniline Compounds/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Pyrimidines/chemistry , Reverse Transcriptase Inhibitors/chemical synthesis , Aniline Compounds/chemistry , Aniline Compounds/toxicity , Cell Line , Chlorine/chemistry , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , Humans , Mutation , Pyrimidines/chemical synthesis , Pyrimidines/toxicity , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/toxicity , Structure-Activity RelationshipABSTRACT
A novel series of naphthyl phenyl ether analogues (NPEs) have been synthesized and evaluated for their in vitro activities against HIV in C8166 cells. Most of the compounds exhibited moderate to excellent anti-HIV activities. Among them the most active compound 12o showed excellent activities against wild-type HIV-1 with an EC(50) value of 4.60 nM, along with moderate activities against the double mutant strain HIV-1(IIIB) A17 (K103N+Y181C) and HIV-2 strain ROD with an EC(50) value of 0.82 and 4.40 µM, respectively. Preliminary structure-activity relationship (SAR) among the newly synthesized NPEs was also investigated.
Subject(s)
Ethers/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/pharmacology , Cell Line , Ethers/chemical synthesis , Ethers/chemistry , HIV-1/drug effects , Humans , Models, Molecular , Molecular Structure , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of (±)-benzhydrol derivatives featuring the essential sulfonamide group at the para position on the C-ring were synthesized and evaluated for the potential anti-HIV activity in C8166 cells. Most of these analogues demonstrated low concentration inhibitory activity with EC(50) values less than 1 µM against the wild-type HIV-1. In particular, compound 7h was identified as the highest active inhibitor of wild-type HIV-1 with an EC(50) value of 0.12 µM and selectivity index value of 312.73. Furthermore, some of them also exhibited moderate activity against the double mutant strain A(17) (K103N+Y181C) with EC(50) values lower than 5 µM. In addition, the binding modes with RT and the preliminary structure-activity relationships of these derivatives were also explored for further chemical modifications.