Synthesis and pharmacological evaluation of naftopidil-based arylpiperazine derivatives containing the bromophenol moiety.

BACKGROUND: Prostate cancer (PCa) is the most common malignancy in men and in the absence of any effective treatments available. METHODS: For the development of potential anticancer agents, 24 kinds of naftopidil-based arylpiperazine derivatives containing the bromophenol moiety were synthesized and characterized by using spectroscopic methods. Their pharmacological activities were evaluated against human PCa cell lines (PC-3 and LNCaP) and a1-adrenergic receptors (a1-ARs; α1a, α1b, and α1d-ARs). The structure-activity relationship of these designed arylpiperazine derivatives was rationally explored and discussed. RESULTS: Among these derivatives, 3c, 3d, 3h, 3k, 3o, and 3s exhibited the most potent activity against the tested cancer cells, and some derivatives with potent anticancer activities exhibited better a1-AR subtype selectivity than others did (selectivity ratio > 10). CONCLUSION: This work provided a potential lead compound for the further development of anticancer agents for PCa therapy.

Identification of benzo[cd]indol-2(1H)-ones as novel Atg4B inhibitors via a structure-based virtual screening and a novel AlphaScreen assay.

Targeting autophagy is a promising therapeutic strategy for cancer treatment. As a result, the identification of novel autophagy inhibitors is an emerging field of research. Herein, we report the development of a novel AlphaScreen HTS assay that combined with a MS-based assay and a structure-based high-throughput virtual screening have enabled the identification of benzo[cd]indol-2(1H)-one as a novel scaffold that targets Atg4B. Thus, an initial screening campaign led to the identification of NSC126353 and NSC611216 bearing a chlorohydrin moiety. Structural-activity relationship analysis of the initial hits provided an optimized lead, compound 33, bearing a 7-aminobenzo[cd]indol-2-[1H]-one scaffold and a propyl group replacing the chlorine. Inhibition of autophagy was also investigated in cells by measuring LC3-II and p62 protein levels. Moreover, the synergistic effect of 33 combined with oxaliplatin resulted in an enhanced cell death in the human colorectal adenocarcinoma cell line HT-29. We are convinced that the developed AlphaScreen and MS-based assays can be key tools enabling the high-throughput identification of novel Atg4B inhibitors. Moreover, the aminobenzo[cd]indol-2-[1H]-one scaffold represents a novel chemotype for the further development of small molecule inhibitors of Atg4B.

Design, synthesis, and antibacterial evaluation of novel derivatives of NPS-2143 for the treatment of methicillin-resistant S. aureus (MRSA) infection.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant global health challenge due to the emergence of strains exhibiting resistance to nearly all classes of antibiotics. This necessitates the rapid development of novel antimicrobials to circumvent this critical problem. Screening of compounds based on phenotypes is one of the major strategies for finding new antibiotics at present. Hence, we here performed a phenotypic screening against MRSA and identified NPS-2143 exhibiting activity against MRSA with an MIC value of 16 µg ml-1. In order to discover more potent anti-MRSA agents, a series of derivatives of NPS-2143 were designed and synthesized. The most promising compounds 48 and 49 exhibited favorable antimicrobial activity with an MIC value of 2 µg ml-1.

New 4-methoxy-naphthalene derivatives as promisor antifungal agents for paracoccidioidomycosis treatment.

AIM: Novel 4-methoxy-naphthalene derivatives were synthesized based on hits structures in order to evaluate the antifungal activity against Paracoccidioides spp. METHODS: Antifungal activity of compounds was evaluated against P. brasiliensis and most promising compounds 2 and 3 were tested against eight clinically important fungal species. RESULTS: Compound 3 was the more active compound with MIC 8 to 32 µg.ml-1 for Paracoccidioides spp without toxicity monkey kidney and murine macrophagecells. Carbohydrazide 3 showed good synergistic antifungal activity with amphotericin B against P. brasiliensis specie. Titration assay of carbohydrazide 3 with PbHSD enzyme demonstrates the binding ligand-protein. Molecular dynamics simulations show that ligand 3 let the PbHSD protein more stable. CONCLUSION: New carbohydrazide 3 is an attractive lead for drug development to treat paracoccidioidomycoses.

Total Synthesis and Structure Revision of Palmarumycin B6.

Palmarumycin B6 and its regioisomer were synthesized via 7- and 13-step routes using 2-chlorophenol and 4-chlorophenyl methyl ether as the starting materials in overall yields of 2.7% and 12%, respectively. Their structures were characterized by 1H and 13C NMR, HRESIMS, and X-ray diffraction data. The structure of palmarumycin B6 was revised as 6-chloropalmarumycin CP17. The bioassay results showed that the larvicidal activity of palmarumycin B6 with an LC50 value of 32.7 µM was significantly higher than that of its 8-chloro isomer, with an LC50 value of 227.3 µM.

Design, synthesis, docking studies and biological screening of 2-thiazolyl substituted -2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines as potent HIV-1 reverse transcriptase inhibitors.

1,3-oxazine nucleus and thiazolyl group features prominently in many biologically important natural products as well as bioactive molecules. A series of novel 2-thiazolyl substituted-2,3-dihydro-1H-naphtho [1,2-e][1,3]oxazine derivatives were designed and synthesized based on their structure-activity relationships (SARs) from 2-naphthol, substituted thiazolyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were first evaluated for their inhibitory effect on HIV-1 Reverse Transcriptase (RT) enzyme activity. Out of 14 compounds, 4 showed potent inhibition of HIV-1 RT activity at significantly low concentration. Docking studies of these molecules revealed their high affinity binding to several amino acids of HIV-1 RT which are less sensitive to point mutations. Furthermore, anti-HIV activity of these molecules was analysed in a CD4+ T cell-line, which indicates that Therapeutic Index (TI) of some of these compounds is better than Zidovudine and Efavirenz, known HIV-1 RT inhibitors. Taken together, our studies report for the first time some novel naphthoxazine derivatives with significant TI, which is through inhibition of HIV-1 RT activity.

Asymmetric synthesis of N-allylic indoles via regio- and enantioselective allylation of aryl hydrazines.

The asymmetric synthesis of N-allylic indoles is important for natural product synthesis and pharmaceutical research. The regio- and enantioselective N-allylation of indoles is a true challenge due to the favourable C3-allylation. We develop here a new strategy to the asymmetric synthesis of N-allylic indoles via rhodium-catalysed N-selective coupling of aryl hydrazines with allenes followed by Fischer indolization. The exclusive N-selectivities and good to excellent enantioselectivities are achieved applying a rhodium(I)/DTBM-Segphos or rhodium(I)/DTBM-Binap catalyst. This method permits the practical synthesis of valuable chiral N-allylated indoles, and avoids the N- or C-selectivity issue.

Selenium-Mediated Synthesis of Tetrasubstituted Naphthalenes through Rearrangement.

New ß-keto ester substituted stilbene derivatives have been synthesized and cyclized with selenium electrophiles in the presence of Lewis acids. This now allows access to 1,2,3,4-tetrasubstituted naphthalene derivatives as cyclization and rearrangement products.

Synthesis of 2-acetyl-1,4-dimethoxynaphthalene, a potential intermediate for disubstituted naphtho[2,3,c]pyran-5,10-dione.

2-Acetyl-1-hydroxynaphthalene was converted into the title compound in three steps (bromination, substitution and methylation). 1-Methoxynaphthalene on bromination, substitution and acetylation, respectively, also yielded the target compound.

Design, synthesis and evaluation of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives as BACE-1 inhibitors.

Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as ß-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 µΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model.

DYZ-2-90, a novel neo-tanshinlactone ring-opened compound, induces ERK-mediated mitotic arrest and subsequent apoptosis by activating JNK in human colorectal cancer cells.

Over the past several decades, there has been a considerable and still growing interest in discovering natural products with anticancer potential from traditional Chinese medicine and increasing their anticancer selectivity by chemical modification. In addition, total synthesis of active compounds from natural products can overcome problems related to poor resource availability. DYZ-2-90 is a novel ring-opened compound modified from neo-tanshinlactone, which is isolated from Chinese medicinal herb tanshen. Both in vitro and in vivo tubulin polymerization assays showed that DYZ-2-90 directly bound to microtubules and rapidly induced tubulin depolymerization, inducing ERK-mediated mitotic arrest and subsequent apoptosis by JNK activation in cancer cells, respectively. These results suggest that the fate of cells that undergo mitotic arrest is dictated by two competing networks activated by DYZ-2-90: the cytoprotective ERK pathway and the stress-related JNK pathway. DYZ-2-90 is therefore a novel microtubule-destabilizing agent and a new drug candidate for cancer therapy. This paper provides a new insight into the model of mitotic cell death, which was proposed in order to elucidate how cancer cells respond to microtubule-interfering agents and prolonged cell cycle delay.

Discovery and structure-activity relationships of urea derivatives as potent and novel CCR3 antagonists.

The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.

Nickel(II)-induced excimer formation of a naphthalene-based fluorescent probe for living cell imaging.

Ni(2+)-induced intramolecular excimer formation of a naphthalene-based novel fluorescent probe, 1-[(naphthalen-3-yl)methylthio]-2-[(naphthalen-6-yl)methylthio]ethane (L), has been investigated for the first time and nicely demonstrated by excitation spectra, a fluorescence lifetime experiment, and (1)H NMR titration. The addition of Ni(2+) to a solution of L (DMSO:water = 1:1, v/v; λ(em) = 345 nm, λ(ex) = 280 nm) quenched its monomer emission, with subsequent enhancement of the excimer intensity (at 430 nm) with an isoemissive point at 381 nm. The fluorescence lifetime of free L (0.3912 ns) is much lower than that of the nickel(2+) complex (1.1329 ns). L could detect Ni(2+) as low as 1 × 10(-6) M with a fairly strong binding constant, 2.0 × 10(4) M(-1). Ni(2+)-contaminated living cells of plant origin could be imaged using a fluorescence microscope.

Synthesis, reactions and biological evaluation of some new naphtho[2,1-b]furan derivatives bearing a pyrazole nucleus.

Vilsmeier formylation of 2-(1-phenylhydrazonoethyl)naphtho[2,1-b]furan (2) gave 3-naphtho[2,1-b]furan-2-yl-1-phenyl-1H-pyrazole-4-carbaldehyde (3), which was reacted with C- and N-nucleophiles to afford naphthofuranpyrazol derivatives 4-8. Treatment of 2-[(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene]-malononitrile (4a) with reactants having active hydrogen and Et3N gave the corresponding pyrazoline, pyran and chromene addition product derivatives 10, 12 and 13, consisting of three different connected heterocyclic moieties. Reaction of 1-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) methylene)-2-phenylhydrazone (6b) with AcONa and ethyl bromoacetate or chloroacetone afforded the thiazolidinone and methylthiazole derivatives 14 and 15, respectively. In addition, intramolecular cyclization of 6d with Ac2O afford the corresponding 1,3,4-thiadiazol-2-yl acetamide derivative 16. The structures of the synthesized compounds were confirmed by IR, ¹H-NMR/¹³C-NMR and mass spectral studies. Compound 14 showed promising effects against the tested Gram positive and negative bacteria and fungi.

Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors.

The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.

Novel quinoline and naphthalene derivatives as potent antimycobacterial agents.

We have designed and synthesized both the quinoline and naphthalene based molecules influenced by the unique structural make-up of mefloquine and TMC207, respectively. These compounds were evaluated for their anti-mycobacterial activity against drug sensitive Mycobacterium tuberculosis H37Rv in vitro at single-dose concentration (6.25 microg/mL). The compounds 22, 23, 26 and 27 inhibited the growth of M. tuberculosis H37Rv 99%, 90%, 98% and 91% respectively. Minimum inhibitory concentration of compounds 22, 23, 26 and 27 was found to be 6.25 microg/mL. Our molecular modeling and docking studies of designed compounds showed hydrogen bonding with Glu-61, Tyr-64 and Asn-190 amino acid residues at the putative binding site of ATP synthase, these interactions were coherent as shown by Mefloquine and TMC207, where hydrogen bonding was found with Tyr-64 and Glu-61 respectively. SAR analysis indicates importance of hydroxyl group and nature of substituents on piperazinyl-phenyl ring was critical in dictating the biological activity of newly synthesized compounds.

Synthesis of daldinol and nodulisporin A by oxidative dimerization of 8-methoxynaphthalen-1-ol.

The synthesis of two natural products, the para-para dimer of 8-methoxynaphthalen-1-ol (2), daldinol (3), and the related ortho-para dimer nodulisporin A (4) was achieved by the oxidation of 2 with ammonium metapervanadate (NH4VO3).

Boronic acid converters for reactive hydrazide amplifiers: polyphenol sensing in green tea with synthetic pores.

Multicomponent sensing in complex matrices with synthetic pores became feasible with the introduction of amplifiers. Amplifiers are defined as molecules that can covalently capture undetectable analytes after enzymatic signal generation and drag them into the pore for transduction. Here, we introduce converters as molecules that can shift the reactivity of amplifiers in situ to capture chemoorthogonal analytes. For this purpose, a series of dialkoxynaphthalene (DAN) and dialkoxyanthracene (DAA) hydrazinoboronic acids was prepared in situ from DAN and DAA hydrazides and formylphenylboronic acids. These converted amplifiers efficiently inactivate synthetic pores with internal naphthalenediimide clamps. This pore inactivation by DAN and DAA hydrazinoboronic acids vanishes in the presence of catechols such as (+)-catechin, presumably because the obtained boronate esters are too large to bind within the synthetic beta-barrel pore or because they prefer to partition into the bilayer membrane. The resulting increase in pore activity with increasing catechol concentration at constant amplifier concentration is shown to be compatible with the sensing of polyphenols in green tea.

Synthesis and evaluation of 4-amino-3,4-dihydro-2H-naphthalen-1-one derivatives as mast cell stabilising and anti-inflammatory compounds.

A novel series of amine and amide derivatives of 4-amino-3,4-dihydro-2H-naphthalen-1-one were synthesised. The amine derivatives were evaluated for mast cell stabilising activity in rodent mast cell preparations against the reference compound disodium cromoglycate and found to possess significant activity in vitro. The amide compounds were evaluated in an in vivo murine model for anti-inflammatory activity.

Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.

We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.