Synthesis of 1,5-diarylhaloimidazole analogs and their inhibitory activities against PGE2 production from LPS-treated RAW 264.7 cells

A number of 1,5-diarylimidazole analogs were synthesized and evaluated their inhibitory activities of cyclooxygenase-2 catalyzed prostaglandin E₂ production. Reactions of 1,5-diarylimidazoles with halogenating reagents (NCS, NBS, NIS) afforded halogenated analogs. Among the analogs tested, compounds Ib, IIa, IIb and IIe exhibited significantly improved inhibitory activities against COX-2-mediated PGE₂ production from LPS-induced RAW 264.7 cells compared to those of the parent 1,5-diarylimidazoles. Especially, the analogs Ib (IC₅₀ = 0.55 μM) and IIa (IC₅₀ = 0.58 μM) showed best results. Halogenation on the 1,5-diarylimidazole ring enhanced inhibitory activities against COX-2 catalyzed PGE₂ production, however, inhibitory activities were significantly varied by position(s) and species of the substituted halogen(s).     

Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H]dopamine uptake

Lobelane analogs that incorporate a central piperidine or pyrrolidine moiety have previously been reported by our group as potent inhibitors of VMAT2 function. Further central ring size reduction of the piperidine moiety in lobelane to a four-membered heterocyclic ring has been carried out in the current study to afford novel cis-and trans-azetidine analogs. These azetidine analogs (15a–15c and 22a–22c) potently inhibited [³H]dopamine (DA) uptake into isolated synaptic vesicles (K_i ? 66 nM). The cis-4-methoxy analog 22b was the most potent inhibitor (K_i = 24 nM), and was twofold more potent that either lobelane (2a, K_i = 45 nM) or norlobelane (2b, K_i = 43 nM). The trans-methylenedioxy analog, 15c (K_i = 31 nM), was equipotent with the cis-analog, 22b, in this assay. Thus, cis- and trans-azetidine analogs 22b and 15c represent potential leads in the discovery of new clinical candidates for the treatment of methamphetamine abuse.     

Synthesis and biological evaluation of phloridzin analogs as human concentrative nucleoside transporter 3 (hCNT3) inhibitors

Nucleoside transporter inhibitors have potential therapeutic applications as anticancer, antiviral, cardioprotective and neuroprotective agents. Although quite a few potent inhibitors of the equilibrative nucleoside transporters are known, largely missing are the concentrative nucleoside transporter inhibitors. Phloridzin (3, K_i = 16.00 μM) is a known moderate inhibitor of the concentrative nucleoside transporters. We have synthesized and evaluated analogs of phloridzin at the hCNT3 nucleoside transporter. Within the series of synthesized analogs compound 16 (K_i = 2.88 μM), possessing a ribofuranose sugar unit instead of a glucopyranose as present in phloridzin, exhibited the highest binding affinity at the hCNT3 transporter. Phloridzin and compound 16 have also been shown to be selective for the hCNT3 transporter as compared with the hENT1 transporter. Compound 16 can serve as a new lead which after further modifications could yield selective and potent hCNT3 inhibitors.     

Lobeline esters as novel ligands for neuronal nicotinic acetylcholine receptors and neurotransmitter transporters

Vesicular monoamine transporter-2 (VMAT2) is a viable target for development of pharmacotherapies for psychostimulant abuse. Lobeline (1) is a potent antagonist at α4β21 nicotinic acetylcholine receptors, has moderate affinity (K_i = 5.46 μM) for VMAT2, and is being investigated currently as a clinical candidate for treatment of psychostimulant abuse. A series of carboxylic acid and sulfonic acid ester analogs 2–20 of lobeline were synthesized and evaluated for interaction with α4β21 and α71 neuronal nicotinic acetylcholine receptors (nAChRs), the dopamine transporter (DAT), serotonin transporter (SERT) and VMAT2. Both carboxylic acid and sulfonic acid esters had low affinity at α71 nAChRs. Similar to lobeline (K_i = 4 nM), sulfonic acid esters had high affinity at α4β21 (K_i = 5–17 nM). Aromatic carboxylic acid ester analogs of lobeline (2–4) were 100–1000-fold less potent than lobeline at α4β21 nAChRs, whereas aliphatic carboxylic acid ester analogs were 10–100-fold less potent than lobeline at α4β21. Two representative lobeline esters, the 10-O-benzoate (2) and the 10-O-benzenesulfonate (10) were evaluated in the ³⁶Rb⁺ efflux assay using rat thalamic synaptosomes, and were shown to be antagonists with IC₅₀ values of 0.85 μM and 1.60 μM, respectively. Both carboxylic and sulfonic acid esters exhibited a range of potencies (equipotent to 13–45-fold greater potency compared to lobeline) for inhibiting DAT and SERT, respectively, and like lobeline, had moderate affinity (K_i = 1.98–10.8 μM) for VMAT2. One of the more interesting analogs, p-methoxybenzoic acid ester 4, had low affinity at α4β21 nAChRs (K_i = 19.3 μM) and was equipotent with lobeline, at VMAT2 (K_i = 2.98 μM), exhibiting a 6.5-fold selectivity for VMAT2 over α4β2 nAChRs. Thus, esterification of the lobeline molecule may be a useful structural modification for the development of lobeline analogs with improved selectivity at VMAT2.     

Relationships between the structure of 6-allyl-6,8-diazabicyclo[3.2.2]nonane derivatives and their σ receptor affinity and cytotoxic activity

A series of bridged piperazine derivatives was prepared and the affinity toward σ₁ and σ₂ receptors by means of radioligand binding assays as well as the inhibition of the growth of six human tumor cell lines was investigated. All possible stereoisomers of the 2-hydroxy, 2-methoxy, 2,2-dimethoxy, 2-oxo, and 2-unsubstituted 6,8-diazabicyclo[3.2.2]nonanes were prepared in a chiral pool synthesis starting with (S)- and (R)-glutamate. A Dieckmann analogous cyclization was the key step in the synthesis of the bicyclic framework. The configuration in position 2 was established by a diastereoselective LiBH₄ reduction and subsequent Mitsunobu inversion. Structure–affinity relationships demonstrate that substituents in position 2 decrease σ₁ receptor affinity which might be due to unfavorable interactions with the σ₁ receptor protein. Without a substituent in position 2 high σ₁ affinity was obtained (23a ((+)-(1S,5S)-6-allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane): K_i = 11 nM). Experiments with six human tumor cell lines showed a weak but selective growth inhibition of the human small cell lung cancer cell line A-427 by the methyl ethers ent-16b (IC₅₀ = 18.9 μM), 21a (IC₅₀ = 16.4 μM), ent-21a (IC₅₀ = 20.4 μM), and 21b (IC₅₀ = 27.1 μM) and the unsubstituted compounds 23a and 23b (42% inhibition at 20 μM).     

Synthesis,anti-HIV activity,integrase enzyme inhibition and molecular modeling of catechol,hydroquinone and quinol labdane analogs

Labdane analogs with o-quinol, catechol and hydroquinone moiety have been synthesized using Diels–Alder reaction of methyl 3,4-dioxocyclohexa-1,5-diene-carboxylate, 3,4-dioxocyclohexa-1,5-diene-carboxylic acid and 3,6-dioxocyclohexa-1,4-dienecarboxylic acid with mono terpene 1,3-dienes, namely ocimene and myrcene. The resulting molecules and their derivatives were evaluated for their anti-HIV-1 activity using TZM-bl cell based virus infectivity assay. Two molecules 13 and 18 showed anti-HIV activity with IC₅₀ values 5.0 (TI = 11) and 4.6 (TI = 46) μM, respectively. The compounds 17, 18 and 20 showed efficacy against HIV-1 integrase activity and showed inhibition with IC₅₀ 13.4, 11.1 and 11.5 μM, respectively. The HIV-1 integrase inhibition activity of these synthetic molecules was comparable with integric acid, the natural fungal metabolite. Molecular modeling studies for the HIV-1 integrase inhibition of these active synthetic molecules indicated the binding to the active site residues of the enzyme.     

Competitive antagonism of insect GABA receptors by iminopyridazine derivatives of GABA

A series of 4-(6-imino-3-aryl/heteroarylpyridazin-1-yl)butanoic acids were synthesized and examined for antagonism of GABA receptors from three insect species. When tested against small brown planthopper GABA receptors, the 3,4-methylenedioxyphenyl and the 2-naphthyl analogues showed complete inhibition of GABA-induced fluorescence changes at 100 μM in assays using a membrane potential probe. Against common cutworm GABA receptors, these analogues displayed approximately 86% and complete inhibition of GABA-induced fluorescence changes at 100 μM, respectively. The 4-biphenyl and 4-phenoxyphenyl analogues showed moderate inhibition at 10 μM in these receptors, although the inhibition at 100 μM was not complete. Against American cockroach GABA receptors, the 4-biphenyl analogue exhibited the greatest inhibition (approximately 92%) of GABA-induced currents, when tested at 500 μM using a patch-clamp technique. The second most active analogue was the 2-naphthyl analogue with approximately 85% inhibition. The 3-thienyl analogue demonstrated competitive inhibition of cockroach GABA receptors. Homology modeling and ligand docking studies predicted that hydrophobic 3-substituents could interact with an accessory binding site at the orthosteric binding site.     

Synthesis and biological evaluation of indole derivatives as α-amylase inhibitor

A series of twenty indole hydrazone analogs (1–21) were synthesized, characterized by different spectroscopic techniques such as ¹H NMR and EI-MS, and screened for α-amylase inhibitory activity. All analogs showed a variable degree of α-amylase inhibition with IC₅₀ values ranging between 1.66 and 2.65 μM. Nine compounds that are 1 (2.23 ± 0.01 μM), 8 (2.44 ± 0.12 μM), 10 (1.92 ± 0.12 μM), 12 (2.49 ± 0.17 μM), 13 (1.66 ± 0.09 μM), 17 (2.25 ± 0.1 μM), 18 (1.87 ± 0.25 μM), 20 (1.83 ± 0.63 μM), and 19 (1.97 ± 0.02 μM) showed potent α-amylase inhibition when compared with the standard acarbose (1.05 ± 0.29 μM). Other analogs showed good to moderate α-amylase inhibition. The structure activity relationship is mainly focusing on difference of substituents on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.     

Design and synthesis of silicon-containing tubulin polymerization inhibitors: Replacement of the ethylene moiety of combretastatin A-4 with a silicon linker

Silicon-containing combretastatin analogs were designed, synthesized and evaluated for stability and biological activities. Among them, compound 31 exhibited strong tubulin polymerization-inhibitory activity and very potent tumor cell growth-inhibitory activity (IC₅₀ = 0.007 μM) in MCF-7 cell proliferation assay. This compound also potently inhibited [³H]colchicine binding (90.7% inhibition at 3 μM). These activities were comparable to those of combretastatin A-4 (CA-4) (1). In addition, compound 31 was physico-chemically more stable than 1. These results suggest that a silicon linker can act as a bioisoster of a cis carbon–carbon double bond.     

Synthesis and biological evaluation of novel 3,4-diaryl lactam derivatives as triple reuptake inhibitors

A series of 3,4-diarylpyrrolidin-2-one was designed, prepared and evaluated as triple reuptake inhibitors for antidepressant. Most compounds exhibited comparable in vitro efficacy as norepinephrine and dopamine transporter reuptake inhibitors. Especially, 2i showed better potency than GBR-12909 (IC₅₀ = 14 nM) which was used as reference compound for dopamine transporter. In addition, 2a and 2b showed inhibition (5.17 μM–85.6 nM) for three transporters.     

Aplysinopsin analogs: Synthesis and anti-proliferative activity of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones

A series of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione (3) analogs structurally related to aplysinopsin, and that incorporate a variety of substituents in both the indole and N-benzyl moieties have been synthesized under microwave irradiation and conventional heating methods These analogs were evaluated for their anti-proliferative activity against MCF-7 and MDA-231 breast cancer cell lines, and A549 and H460 lung cancer cell lines. Two analogs, 3f and 3j had IC₅₀ values of 4.4 and 5.2 μM, respectively, compared to 5-fluorouracil (IC₅₀ = 15.2 μM) against MCF-7 cells.     

Regiospecific and conformationally restrained analogs of melphalan and dl-2-NAM-7 and their affinities for the large neutral amino acid transporter (system LAT1) of the blood–brain barrier

Regiospecific and conformationally restrained analogs of melphalan and dl-2-NAM-7 have been synthesized and their affinities for the large neutral amino acid transporter (LAT1) of the blood–brain barrier have been determined to assess their potential for accessing the CNS via facilitated transport. Several analogs had K_i values in the range 2.1–8.5 μM with greater affinities than that of either l-phenylalanine (K_i = 11 μM) or melphalan (K_i = 55 μM), but lower than dl-2-NAM-7 (K_i = 0.08 μM). The results indicate that regiospecific positioning of the mustard moiety on the aromatic ring in these analogs is very important for optimal affinity for the large neutral amino acid transporter, and that conformational restriction of the dl-2-NAM-7 molecule in benzonorbornane and indane analogs leads to 25- to 60-fold loss, respectively, in affinity.     

Synthesis of novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives via domino aldol-type/hetero Diels–Alder reaction and their cytotoxicity evaluation

New chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives have been synthesized by domino aldol-type reaction/hetero Diels–Alder reaction generated from o-quinone methide in situ from 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones with resorcinols/naphthols in the presence of 20 mol % ethylenediamine diacetate (EDDA), triethylamine (2 mL) as co-catalyst in CH₃CN under reflux conditions in good yields. The structures were established based on spectroscopic data, and further confirmed by X-ray diffraction analysis. The results showed that compounds 4h and 4j exhibited very potent cytotoxicity against human cervical cancer cell line (HeLa). Compound 4h displayed good inhibitory activity against both breast cancer cell lines, MDA-MB-231 and MCF-7. Further, the compound 4i exhibited good cytotoxicity against only MDA-MB-231, and compound 4j showed promising activity against human lung cancer cell line, A549 with IC₅₀ value of 2.53 ± 0.07 μM, which was comparable to the standard doxorubicin (IC₅₀ = 1.21 ± 0.1 μM).     

Isatin based Schiff bases as inhibitors of α-glucosidase: Synthesis,characterization, in vitro evaluation and molecular docking studies

Isatin base Schiff bases (1–20) were synthesized, characterized by ¹H NMR and EI/MS and evaluated for α-glucosidase inhibitory potential. Out of these twenty (20) compounds only six analogs showed potent α-glucosidase inhibitory potential with IC₅₀ value ranging in between 2.2 ± 0.25 and 83.5 ± 1.0 μM when compared with the standard acarbose (IC₅₀ = 840 ± 1.73 μM). Among the series compound 2 having IC₅₀ value (18.3 ± 0.56 μM), 9 (83.5 ± 1.0 μM), 11 (3.3 ± 0.25 μM), 12 (2.2 ± 0.25 μM), 14 (11.8 ± 0.15 μM), and 20 (3.0 ± 0.15 μM) showed excellent inhibitory potential many fold better than the standard acarbose. The binding interactions of these active analogs were confirmed through molecular docking.     

Synthesis and anticancer activity of sclerophytin-inspired hydroisobenzofurans

Three structurally related sets of hydroisobenzofuran analogs of sclerophytin A were prepared in three or four steps from (S)-(+)-carvone via an aldol-cycloaldol sequence. The most potent members of each set of analogs exhibited IC₅₀’s of 1–3 μM in growth inhibitory assays against KB3 cells. The NCI 60-cell line 5-dose assay for analog 6h revealed a GI₅₀ = 0.148 μM and LC₅₀ = 9.36 μM for the RPMI-8226 leukemia cell line, and a GI₅₀ = 0.552 μM and LC₅₀ = 26.8 μM for the HOP-92 non-small cell lung cancer cell line.     

Design and synthesis of l- and d-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase

Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC₅₀ = 7.7 μM) and 2 (IC₅₀ = 10.6 μM) as represented by hybrid compound 27 (IC₅₀ = 6.7 μM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC₅₀ of 2.6 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the d-isomers 41 (IC₅₀ = 19.3 μM) and 45 (IC₅₀ = 5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition.     

Bacterial Peptide deformylase inhibition of cyano substituted biaryl analogs: Synthesis,in vitro biological evaluation,molecular docking study and in silico ADME prediction

Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a–m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC₅₀ value = 13.16 μM), 5d (IC₅₀ value = 15.66 μM) and 5j (IC₅₀ value = 19.16 μM) had shown good PDF inhibition activity. The compounds 5a (MIC range = 11.00–15.83 μg/mL), 5b (MIC range = 23.75–28.50 μg/mL) and 5j (MIC range = 7.66–16.91 μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range = 25–50 μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(a–m) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.     

Xanthine oxidase inhibitors isolated from Piper nudibaccatum

Two new hydroxychavicol analogs nudibaccatumin A (1) and B (2), together with twenty known compounds were isolated from the methanol extract of Piper nudibaccatum. Their structures were elucidated by extensive spectroscopic analyses (1D and 2D NMR, HRESIMS, UV, IR and polarimetry). Hydroxychavicol is a known inhibitor of xanthine oxidase (XO). In the present study, hydroxychavicol and 5 natural analogs (1–5) were evaluated for their XO inhibitory activity. Neotaiwanensol B (3) (IC₅₀ = 0.28 μM) showed a greater inhibitory effect than hydroxychavicol and allopurinol (the positive control). Two new compounds 1 and 2 showed a moderate inhibition activity with an IC₅₀ value of 62.94 μM and 70.67 μM, respectively.     

Relationships between the structure of 6-substituted 6,8-diazabicyclo[3.2.2]nonan-2-ones and their σ receptor affinity and cytotoxic activity

A series of 2-oxo-6,8-diazabicyclo[3.2.2]nonane derivatives was prepared and the affinity towards σ₁ and σ₂ receptors was investigated by means of radioligand binding assays as well as their inhibition of the growth of six human tumor cell lines was studied. Starting from the enantiopure bicyclic ketones 3 and ent-3 bridged piperazines with different residues in position 6 were synthesized. The N-6 allyl protective group was removed by a RhCl₃ catalyzed double bond isomerization and subsequent hydrolysis of the resulting enamide 8. After acetalization the secondary amide 10 was alkylated and arylated. Structure affinity relationships show that a relatively large substituent, which has not necessarily to be an aromatic one, is required in position 6 for high σ₁ receptor affinity (e.g., 12 and ent-12 with a dimethylallyl residue: K_i = 20 nM and 17 nM). Furthermore, it was shown that substituents that reduce the basicity of N-6 led to a severe decrease in σ₁ affinity. Growth inhibition experiments with six human tumor cell lines revealed that the allyl and benzyl substituted 6,8-diazabicyclo[3.2.2]nonan-2-one derivatives 5, ent-5 and ent-14 are able to selectively inhibit the growth of the bladder cancer cell line 5637.     

Synthesis and activity of novel tetrazole compounds and their pyrazole-4-carbonitrile precursors against Leishmania spp

A new series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a–m) and their precursor 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a–m) were synthesized and evaluated as antileishmanials against Leishmania braziliensis and Leishmania amazonensis promastigotes in vitro. In parallel, the cytotoxicity of these compounds was evaluated on the RAW 264.7 cell line. The results showed that among the assayed compounds the substituted 3-chlorophenyl (4a) (IC₅₀/24 h = 15 ± 0.14 μM) and 3,4-dichlorophenyl tetrazoles (4d) (IC₅₀/24 h = 26 ± 0.09 μM) were the most potent against L. braziliensis promastigotes, as compared the reference drug pentamidine, which presented IC₅₀ = 13 ± 0.04 μM. In addition, 4a and 4d derivatives were less cytotoxic than pentamidine. However, these tetrazole derivatives (4) and pyrazole-4-carbonitriles precursors (3) differ against each of the tested species and were more effective against L.braziliensis than on L. amazonensis.