Synthesis and characterization of novel 1,2-oxazine-based small molecules that targets acetylcholinesterase

Thirteen 2-oxazine-based small molecules were synthesized targeting 5-lipoxygenase (LOX), and acetylcholinesterase (AChE). The test revealed that the newly synthesized compounds had potent inhibition towards both 5-LOX and AChE in lower micro molar concentration. Among the tested compounds, the most active compound, 2-[(2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (2a) showed inhibitory activity towards 5-LOX and AChE with an IC₅₀ values of 1.88, and 2.5 μM, respectively. Further, the in silico molecular docking studies revealed that the compound 2a bound to the catalytic domain of AChE strongly with a highest CDOCKER score of −1.18 kcal/mol when compared to other compounds of the same series. Additionally, 2a showed a good lipophilicity (log P = 2.66), suggesting a potential ability to penetrate the blood–brain-barrier. These initial pharmacological data revealed that the compound 2a could serve as a drug-seed in developing anti-Alzheimer’s agents.     

Novel boronated chlorin e6-based photosensitizers: Synthesis,binding to albumin and antitumour efficacy

Chlorins, a class of plant porphyrins, are perspective as photosensitizing agents due to light absorption in the long wavelength spectral region and deeper photodamage of tissues. Aiming at optimization of antitumour properties of chlorins, we synthesized a series of boronated derivatives of chlorin e₆ and their complexes containing Zn(II), Pd(II) or Sn(IV). The compounds were synthesized by alkylation of amino or hydroxy derivatives of chlorin e₆ with 1-trifluoromethanesulfonylmethyl-o-carborane. Chlorin e₆ 13(1)-N-{2-[N-(o-carboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester (compound 5) formed complexes with serum albumin, a major porphyrin carrier. The binding constant of these complexes was ～4 times bigger than the respective value for the complexes of albumin with boron-free aminochlorin e₆. Compound 5 potently sensitized rat fibroblasts to illumination with monochromatic red light: >98% of cells were necrotic by 24 h post-illumination with 1 μM of 5. This compound demonstrated high efficacy in photodynamic therapy of rat M-1 sarcoma. After PDT with 25 mg/kg of 5 the residual tumours were significantly smaller than in animals subjected to PDT with equal concentration of boron-free aminochlorin e₆. No signs of general toxicity were detectable after PDT with 5. Thus, boronation can enhance the potency of chlorins in PDT, in particular, due to an increased binding to albumin. Our data expand the therapeutic applicability of boronated chlorins beyond boron neutron capture therapy; these agents emerge as dual efficacy photoradiosensitizers.     

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 1,2,4-trisubstituted imidazoles as inhibitors of transforming growth factor-β type I receptor (ALK5)

A series of 2-(6-methylpyridin-2-yl)-1H-imidazoles were synthesized and evaluated for ALK5 inhibitory activity in cell-based luciferase reporter assays. The compound 4-(((1-(benzo[d][1,3]dioxol-5-yl)-2-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)methyl)amino)benzenesulfonamide (27a) exhibited slightly higher inhibition (IC₅₀ = 0.24 μM) than SB431542 (IC₅₀ = 0.35 μM), a well known potent ALK5 inhibitor. The binding mode of 27a generated by flexible docking study shows that it fits well into the site cavity of ALK5 by forming several tight interactions.     

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).     

Structural studies on zinc(II) complexes with 2-benzoylpyridine-derived hydrazones

2-Benzoylpyridine-phenylhydrazone (H2BzPh), 2-benzoylpyridine-para-chloro-phenylhydrazone (H2BzpClPh), and 2-benzoylpyridine-para-nitro-phenyl (H2BzpNO₂Ph) hydrazone were obtained and fully characterized, as well as their zinc(II) complexes [Zn(H2BzPh)Cl₂] (1), [Zn(H2BzClPh)Cl₂] (2) and [Zn(H2BzpNO₂Ph)Cl₂] (3). During the syntheses of complex 1 a second product crystallized, which was characterized as [Zn(2BzPh)₂] (1a). Upon re-crystallization in 1:9 DMSO:acetone conversion of 2 into [Zn(H2BzpClPh)Cl₂] · H₂O (2a) and of 3 into [Zn(2BzpNO₂Ph)Cl(DMSO)] (3a) occurred. The crystal structures of 1a, 2a and 3a were determined. In 1a the two nearly perpendicular H2BzPh ligands give rise to a distorted octahedral environment around the metal. The 5-fold coordination around the metal is completed with two chloride ions in 2a and with one chloride and one oxygen atom from DMSO in 3a.     

Chiral porphyrin complexes of cobalt(II) and ruthenium(II) in catalytic cyclopropanation and amination reactions

We report here the syntheses of two new metal complexes (M = Co, 2; M = Ru, 3) of the chiral porphyrin TmyrtP (1) (TmyrtP = dianion of the meso-tetrakis[(1R)-apopinen-2-yl]porphyrin). Both complexes exist as a mixture of atropisomers. Complexes 2 and 3 activate aromatic azides for the amination under mild conditions of unsaturated hydrocarbons. Even though the observed ee values are low, this is the first asymmetric transfer of the nitrene residue of aryl azides to a prochiral olefin catalyzed by a transition metal complex to be reported in the literature. Complex 3 also showed a good catalytic activity in cyclopropanation reactions with ethyldiazoacetate even at low temperatures (−30 °C) but a poor diastereo- and enantioselectivity were observed.     

Coumarin derivatives as potential inhibitors of acetylcholinesterase: Synthesis,molecular docking and biological studies

A series of novel hybrids has been synthesized by linking coumarin moiety through an appropriate spacer to various substituted heterocyclic amines and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of cognitive dysfunction caused by increased hydrolysis of acetylcholine and scopolamine induced oxidative stress. Anti-amnesic activity of the compounds was evaluated using Morris water maze model at a dose of 1 mg/kg with reference to the standard, donepezil. Biochemical estimation of oxidative stress markers (lipid peroxidation, superoxide dismutase, and plasma nitrite) was carried out to assess the antioxidant potential of the synthesized molecules. Among all the synthesized compounds (15a–i, 16a–d, 17a–b), compound 15a [4-[3-(4-phenylpiperazin-1-yl)propoxy]-2H-chromen-2-one] displayed significant antiamnesic activity, AChE inhibitory activity (IC₅₀ = 2.42 μM) and antioxidant activity in comparison to donepezil (IC₅₀ = 1.82 μM). Molecular docking study of 15a indicated that it interacts with all the crucial amino acids present at the CAS, mid-gorge and PAS of TcAChE resulting in increased inhibition of AChE enzyme.     

Bis-phosphonium salts of pyridoxine: The relationship between structure and antibacterial activity

A series of 23 novel bis-phosphonium salts based on pyridoxine were synthesized and their antibacterial activities were evaluated in vitro. All compounds were inactive against gram-negative bacteria and exhibited the structure-dependent activity against gram-positive bacteria. The antibacterial activity enhanced with the increase in chain length at acetal carbon atom in the order n-Pr > Et > Me. Further increasing of length and branching of alkyl chain leads to the reduction of antibacterial activity. Replacement of the phenyl substituents at the phosphorus atoms in 5,6-bis(triphenylphosphonio(methyl))-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine dichloride (compound 1) with n-butyl, m-tolyl or p-tolyl as well as chloride anions in the compound 1 with bromides (compound 14a) increased the activity against Staphylococcus aureus and Staphylococcus epidermidis up to 5 times (MICs = 1–1.25 μg/ml). But in practically all cases chemical modifications of compound 1 led to the increase of its toxicity for HEK-293 cells. The only exception is compound 5,6-bis[tributylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (10a) which demonstrated lower MIC values against S. aureus and S. epidermidis (1 μg/ml) and lower cytotoxicity on HEK-293 cells (CC₅₀ = 200 μg/ml). Compound 10a had no significant mutagenic and genotoxic effects and was selected for further evaluation. It should be noted that all bis-phosphonium salt based on pyridoxine were much more toxic than vancomycin.     

Biotransformation of isoimperatorin and imperatorin by Glomerella cingulata and β-secretase inhibitory activity

Biotransformation studies conducted on the furanocoumarins isoimperatorin (1) and imperatorin (3) have revealed that 1 was metabolized by Glomerella cingulata to give the corresponding reduced acid, 6,7-furano-5-prenyloxy hydrocoumaric acid (2), and 3 was transformed by G. cingulata to give the dealkylated metabolite, xanthotoxol (4) in high yields (83% and 81%), respectively. The structures of the new compound 2 have been established on the basis of spectral data. The metabolites 2 and 4 were tested for the β-secretase (BACE1) inhibitory activity in vitro, and metabolite 2 slightly inhibited the β-secretase activity with an IC₅₀ value of 185.6 ± 6.8 μM. The metabolite 4 was less potent activity than compounds 1–3. In addition, methyl ester (2Me), methyl ether (2a) and methyl ester and ether (2aMe) of 2 were synthesized, and investigated for the ability to inhibit β-secretase. Compound 2aMe exhibited the best β-secretase inhibitory activity at the IC₅₀ value 16.2 ± 1.2 μM and found to be the 2aMe showed competitive mode of inhibition against β-secretase with K_i value 11.3 ± 2.8 μM.     

Design synthesis and structure–activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands

Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850–4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75 ± 21 nM, and 190 ± 42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170 ± 42 nM, in contrast to its binding affinity results.     

Two new N-heterocyclic carbene silver(I) complexes with the π–π stacking interactions

The precursors bis[N-(alkyl)benzimidazoliumylmethyl]durene halide (1a: alkyl = C₂H₅, halide = Br^?; 1b: alkyl = n-C₄H₉, halide = Cl^?; durene = 1,2,4,5-tetramethylbenzene) and their two new NHC silver(I) complexes [Durene(CH₂BimyEtAgBr)₂] (2a) and [Durene(CH₂BimyⁿBuAgCl)₂] (2b) (Bimy = benzimidazol-2-ylidene) have been prepared and characterized. In the crystal structures of 2a and 2b the aromatic π–π stacking interactions are observed.     

Design,synthesis and evaluation of 6-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenanthridine analogues as antimycobacterial agents

Focus in this Letter is made to design and synthesize a series of nineteen new 6-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenanthridine analogues employing click chemistry and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H₃₇Rv. Among the tested compounds, 7f and 7j exhibited good activity (MIC = 3.125 μg/mL), while 8a displayed excellent activity (MIC = 1.56 μg/mL) against the growth of M. tuberculosis H₃₇Rv. In addition, 7f, 7j and 8a compounds were subjected to cytotoxic studies against mouse macrophage (RAW264.7) cell lines and the selectivity index values are >15 indicating suitability of compounds for further drug development.     

Molecular design,synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2

A group of cyclic imides (1–10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC₅₀ range of 0.1–4.0 μM. In vitro COX-1/COX-2 inhibition structure–activity studies identified compound 8a as a highly potent (IC₅₀ = 0.1 μM), and an extremely selective [COX-2 (SI) > 1000] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED₅₀ = 72.4 mg/kg) relative to diclofenac (ED₅₀ = 114 mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO₂NH₂ group underwent H-bonding interaction with Gln¹⁹²(2.95 Å), Phe⁵¹⁸(2.82 Å) and Arg⁵¹³(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.     

DNA binding and photocleavage properties and apoptosis-inducing activities of a ruthenium porphyrin complex [(Py-3′)TPP-Ru(phen)2Cl]Cl and its heterometallic derivatives

The interactions of a ruthenium porphyrin complex [(Py-3′)TPP-Ru(phen)₂Cl]Cl (phen = 1,10-phenanthroline, (Py-3′)TPP = 5-(3′-pyridyl-10,15,20-triphenylporphyrin) (1) and its heterometallic derivatives, [Ni(Py-3′)TPP-Ru(phen)₂Cl][PF₆] (2) and [Cu(Py-3′)TPP-Ru(phen)₂Cl][PF₆] (3), with calf thymus DNA have been investigated by spectroscopic and viscosity measurements in this study. The results showed that these synthetic complexes can bind to double strand helix DNA in groove binding mode, and the intrinsic binding constants of complexes 1, 2 and 3, as calculated according to the decay of the Soret absorption, are (1.35 ± 0.5) ×10⁵ M^?1 (s = 4.2), (1.29 ± 0.5) × 10⁵ M^?1 (s = 5.6) and (1.22 ± 0.5) × 10⁵ M^?1 (s = 6.2) (s is the binding-site size), respectively, which are consistent with those obtained from ethidium bromide-quenching experiments. Further investigations on the photocleavage properties of these complexes on plasmid pBR 322 DNA showed that complexes 1, 2 and 3 could cleave single chain DNA and convert DNA molecules from supercoiled form to the nicked form. As determined by MTT assay, the complexes were also identified as potent antiproliferative agents against A375 human melanoma cells, MCF-7 human breast adrenocarcinoma cells, Colo201 human colon adenocarcinoma cells and HepG2 human liver cancer cells. Complex 1 inhibits the growth of A375 cells through induction of apoptotic cell death and G0/G1 cell cycle arrest. Further investigation on intracellular mechanisms indicated that Complex 1 induced depletion of mitochondrial membrane potential (ΔΨ_m) in A375 cells through regulating the expression of pro-survival and pro-apoptotic Bcl-2 family members. Our results suggest that ruthenium porphyrin complexes could be candidates for further evaluation as chemopreventive and chemotherapeutic agents for human cancers.     

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.     

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.     

Aerobic oxidation of indolomorphinan without the 4,5-epoxy bridge and subsequent rearrangement of the oxidation product to spiroindolinonyl-C-normorphinan derivative

Aerobic oxidation of indolomorphinan 1 without a 4,5-epoxy bridge proceeded in the presence of platinum catalyst to give indoleninomorphinan 2 or quinolono-C-normorphinan 5. The 4-hydroxy group would play an important role in deciding the course of the reaction. Treatment of 2a with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave spiroindolinonyl-C-normorphinan 3a whose structure resembles that of δ opioid receptor agonist spiroindanyloxymorphone (SIOM). Boron trichloride was effective for the reverse reaction from 3a to 2a without side reaction. This practical interconversion method between hydroxyindolenine and spiroindolinone would be useful for the design and construction of drug-like compound libraries. Although the compound 3b was expected to show the selectivity for δ opioid receptor because of the structural resemblance to SIOM, it was rather selective for μ opioid receptor (μ: K_i = 0.75 nM; δ: K_i = 2.90 nM; κ: K_i = 13.4 nM). The result suggests that the slight difference of the spatial location of the benzene rings in these compounds may definitively affect the binding affinity for δ opioid receptor.     

The beneficial effects of rosuvastatin are independent of zinc supplementation in patients with atherosclerosis

BackgroundStatins have multiple antiatherosclerotic effects, but can reduce blood plasma concentrations of minerals, including zinc. As zinc possesses antiinflammatory and antioxidant effects, low zinc status can promote injuries or inadequate tissue repair in endothelial cells. Metallothionein (MT) expression might modulate responses induced by statins in patients with atherosclerosis. However, research regarding mineral status and the use of statins is scarce. This study evaluated the effects of zinc supplementation on zinc status and expression of the zinc-dependent MT1F and MT2A genes in patients with atherosclerosis treated with rosuvastatin.MethodsA double-blind, randomized clinical trial was performed with 54 participants treated with 10 mg rosuvastatin for 4 months with or without zinc supplementation (30 mg/day). Diet, lipid profile, high-sensitivity reactive protein C (hs-CRP), plasma and erythrocyte zinc concentrations, erythrocyte superoxide dismutase (SOD) activity, and MT1F and MT2A genes expression were analyzed before and after intervention.ResultsRosuvastatin therapy was effective in reducing low- and non-high-density lipoprotein, total cholesterol, triglycerides, and hs-CRP levels, independent of zinc supplementation. Additionally, zinc treatment had no effect on SOD enzyme activity (P = 0.201), plasma (P > 0.671) and erythrocyte (P > 0.123) zinc concentrations, or the pattern of MT1F and MT2A genes expression (P = 0.088 and P = 0.229, respectively).ConclusionsThe effectiveness of rosuvastatin treatment is independent of the effects of zinc supplementation. Moreover, rosuvastatin treatment did not have a significant impact on zinc status or MT1F and MT2A genes expression in patients with atherosclerosis.     

Synthesis and structure–activity relationship of 3β-(4-alkylthio, -methylsulfinyl,and -methylsulfonylphenyl)tropane and 3β-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters

Early studies led to the identification of 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid methyl ester (5) with high affinity at the DAT (IC₅₀ = 6.5 nM) and 5-HTT (K_i = 4.3 nM), while having much less affinity at the NET (K_i = 1110 nM). In the present study, we replaced the 4′-methoxy group of the 3β-phenyl ring with a bioisosteric 4′-methylthio group to give 7a. We also synthesized a number of 3β-(4-alkylthiophenyl)tropanes 7b–e, 3β-(4-methylsulfinylphenyl) and 3β-(4-methylsulfonylphenyl)tropane analogues 7f–h as well as the 3β-(4-alkylthiophenyl)nortropane derivatives 8–11 to further characterize the structure–activity relationship of this type of compound for binding at monoamine transporters. With exception of the 4′-methylsulfonyl analogue 7h, all the tested compounds possessed high binding affinities at the 5-HTT. The K_i values ranged from 0.19 nM to 49 nM. The 3β-(4-methylthiophenyl)tropane 7a and its N-(3-fluoropropyl) analogue 9a and N-allyl analogue 10a are the most selective compounds for the 5-HTT over the NET (NET/5-HTT = 314–364) in the series. However, none of the compounds showed selectivity similar to 5 for both the DAT and 5-HTT relative to the NET. This study provided useful SAR information for rational design of potent and selective monoamine transporter inhibitors.