2-substituted Analogues Research Articles

Novel Analogues of (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Sumanirole) Provide Clues to Dopamine D2/D3 Receptor Agonist Selectivity.

Novel 1-, 5-, and 8-substituted analogues of sumanirole (1), a dopamine D2/D3 receptor (D2R/D3R) agonist, were synthesized. Binding affinities at both D2R and D3R were higher when determined in competition with the agonist radioligand [3H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [3H]N-methylspiperone. Although 1 was confirmed as a D2R-preferential agonist, its selectivity in binding and functional studies was lower than previously reported. All analogues were determined to be D2R/D3R agonists in both GoBRET and mitogenesis functional assays. Loss of efficacy was detected for the N-1-substituted analogues at D3R. In contrast, the N-5-alkyl-substituted analogues, and notably the n-butyl-arylamides (22b and 22c), all showed improved affinity at D2R over 1 with neither a loss of efficacy nor an increase in selectivity. Computational modeling provided a structural basis for the D2R selectivity of 1, illustrating how subtle differences in the highly homologous orthosteric binding site (OBS) differentially affect D2R/D3R affinity and functional efficacy.

Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres

1.The first generation 5HT-4 partial agonist, 4-{4-[4-Tetrahydrofuran-3-yloxy)-benzo[d]isoxazol-3-yloxymethyl]-piperidin-1-ylmethyl}-tetrahydropyran-4-ol, PF-4995274 (TBPT), was metabolized to N-dealkylated (M1) and an unusual, cyclized oxazolidine (M2) metabolites. M1 and M2 demonstrated pharmacological activity at 5HT receptor subtypes warranting further investigation into their dispositional properties in humans; M2 was a minor component in vitro but was the pre-dominant metabolite identified in human plasma.2.To shift metabolism away from the piperidine ring of TBPT, a series of heterocyclic replacements were designed, synthesized, and profiled. Groups including azetidines, pyrrolidines, as well as functionalized piperidines were evaluated with the goal of identifying an alternative group that maintained the desired potency, functional activity, and reduced turnover in human hepatocytes.3.Activities of 4-substituted piperidines or pyrrolidine analogs at the pharmacological target were not significantly altered, but the same metabolic pathways of N-dealkylation and oxazolidine formation were still observed. Altering these to bridged ring systems lowered oxazolidine metabolite formation, but not N-dealkylation.4.The effort concluded with identification of azetidines as second-generation 5HT4 partial agonists. These were neither metabolized via N-dealkylation nor converted to cyclized oxazolidine metabolites rather oxidized on the isoxazole ring. The use of azetidine as a replacement for aliphatic aza-heterocyclic rings in drug design to alter drug metabolism and pharmacology is discussed.

Synthesis, antimicrobial and anti-inflammatory activities of some novel 5-substituted imidazolone analogs

Abstract In view of potent antimicrobial and anti-inflammatory activities exhibited by 5-substituted imidazolones, a variety of novel imidazolone analogs 3a-l were synthesized by the condensation of different substituted oxazolones 1 with various aromatic amines 2. All the synthesized compounds were screened for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several analogs produced good or moderate activities particularly against the tested Gram-positive bacteria Micrococcus luteus and Gram-negative bacteria Pseudomonas aeruginosa and. Meanwhile, compounds 3b and 3c displayed marked antifungal activity against C. albicans. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using the carrageenin-induced paw oedema method in rats. Two of 5-substituted imidazolone derivatives, 3k and 3d show good anti-inflammatory activity. The structures of all the newly synthesized compounds were elucidated using IR, 1H NMR and 13C NMR.

Azide-Incorporated Clickable Silk Fibroin Materials with the Ability to Photopattern.

Incorporation of unnatural amino acids (UAAs) bearing bioorthogonal reactive groups into proteins could be a powerful tool for developing novel protein-based biomaterials with innovative and controlled performance. Bombyx mori silk fibroin is one of naturally derived protein materials extensively studied for biomaterials development due to its mechanical strength and biocompatibility. We recently reported the in vivo incorporation of UAAs, 4-substituted analogues of phenylalanine including 4-azidophenylalanine (AzPhe), into silk fibroin by expanding the repertoire of amino acids for protein biosynthesis in silk glands of B. mori using transgenic techniques. We demonstrated that azide groups in AzPhe incorporated into silk fibroin can be selectively modified by bioorthogonal azide-alkyne cycloaddition reactions (click chemistry). However, the incorporation of AzPhe into silk fibroin required a special feeding condition, which led to the limited production of silk fibroin. Here we report more efficient production of an AzPhe-incorporated silk fibroin (termed AzidoSilk) and its modification by click chemistry in varied material forms (thread, film, and porous sponge). Using this methodology, photolithographic micropatterning of fluorescent molecules directly onto silk fibroin film was achieved and should further expand the availability of silk-based biomaterials for cell culture substrates, drug delivery, tissue scaffolds, implantable devices, and so on.

Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure-Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs.

Many cathinone analogs act as substrates or inhibitors at dopamine, norepinephrine, and serotonin transporters (DAT, NET, SERT, respectively). Drug selectivity at DAT vs. SERT is a key determinant of abuse potential for monoamine transporter substrates and inhibitors, such that potency at DAT > SERT is associated with high abuse potential, whereas potency at DAT < SERT is associated with low abuse potential. Quantitative structure-activity relationship (QSAR) studies with a series of 4-substituted methcathinone analogs identified volume of the 4-position substituent on the methcathinone phenyl ring as one structural determinant of both DAT vs. SERT selectivity and abuse-related behavioral effects in an intracranial self-stimulation procedure in rats. Subsequent modeling studies implicated specific amino acids in DAT and SERT that might interact with 4-substituent volume to determine effects produced by this series of cathinone analogs. These studies illustrate use of QSAR analysis to investigate pharmacology of cathinones and function of monoamine transporters.

Syntheses of 2-substituted 1-amino-4-bromoanthraquinones (bromaminic acid analogues) - precursors for dyes and drugs.

Anthraquinone (AQ) derivatives play a prominent role in medicine and also in textile industry. Bromaminic acid (1-amino-4-bromoanthraquinone-2-sulfonic acid) is an important precursor for obtaining dyes as well as biologically active compounds through the replacement of the C4-bromo substituent with different (ar)alkylamino residues. Here we report methods for the synthesis of bromaminic acid analogues bearing different substituents at the 2-position of the anthraquinone core. 1-Aminoanthraquinone was converted to its 2-hydroxymethyl-substituted derivative which, under different reaction conditions, yielded the corresponding carbaldehyde, carboxylic acid, and nitrile derivatives. The latter was further reacted to obtain 1-amino-2-tetrazolylanthraquinone. Subsequent bromination using bromine in DMF led to the corresponding bromaminic acid derivatives in excellent isolated yields (>90%) and high purities. Alternatively, 1-amino-4-bromo-2-hydroxymethylanthraquinone could be directly converted to the desired 2-substituted bromaminic acid analogues in high yields (85–100%). We additionally report the preparation of bromaminic acid sodium salt and 1-amino-2,4-dibromoanthraquinone directly from 1-aminoanthraquinone in excellent yields (94–100%) and high purities. The synthesized brominated AQs are valuable precursors for the preparation of AQ drugs and dyes.

An efficient green synthesis of 2-arylbenzothiazole analogues as potent antibacterial and anticancer agents.

We have demonstrated a novel and green approach for the synthesis of 2-substituted benzothiazole analogues. A number of 2-aryl and heteroaryl benzothiazole scaffolds were synthesized using Amberlite IR-120 resin under microwave irradiation. The catalytic role and reusability of the resin was well established here. 2-Substituted benzothiazole analogues (3a-l) were also tested against several bacterial strains (Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Salmonella) and cancer cell lines (MCF-7 and HeLa). The stability of compound 2-phenyl benzothiazole (3a) and 2-pyridin-2-yl-benzothiazole (3k) in GSH (0.01mM dissolved in DMSO) was measured by UV-Vis spectroscopy. Compound 3k also shows remarkable fluorescence in MeOH.

Stereoselective yeast-mediated reduction of trans-5-(1'-oxo-3'-methylbutyl)-3-methyldihydrofuran-2-one: production of chiral intermediates for the synthesis of β-secretase inhibitors.

To investigate the usefulness of yeast strains to the production of chiral hydroxylactones, important synthons in the synthesis of β-secretase inhibitors. Strains Rhodotorula glutinis KCh 242, Rhodotorula rubra KCh 82, Rhodotorula marina KCh 77 and Saccharomyces cerevisiae KCh 464 reduced racemic trans-5-(1'-oxo-3'-methylbutyl)-3-methyldihydrofuran-2-one (4) according to the Prelog's rule to afford preferentially the stereoisomers with S configurations at C-1'. R. marina KCh 77 and R. glutinis KCh 242 exhibited selectivity towards 3S, 5R enantiomer of the substrate, whereas R. rubra KCh 82 and S. cerevisiae KCh 464 preferred the reduction of its antipode. The highest yield of 3R,5S,1'S-hydroxylactone 3c (78 %) was obtained with R. rubra KCh 82. Different stereoisomers of trans-5-(1'-hydroxy-3'-methylbutyl)-3-methyldihydrofuran-2-one and its 5-substituted analogues are produced as important intermediates in the synthesis of drugs for the therapy of Alzheimer's disease.

The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor

Selective antagonism of the orexin 1 (OX1) receptor has been proposed as a potential mechanism for treatment of drug addiction. We have previously reported studies on the structure–activity relationships of tetrahydroisoquinoline-based antagonists. In this report, we elucidated the respective role of the 6- and 7-substitutions by preparation of a series of either 6-substituted tetrahydroisoquinolines (with no 7-substituents) or vice versa. We found that 7-substituted tetrahydroisoquinolines showed potent antagonism of OX1, indicating that the 7-position is important for OX1 antagonism (10c, Ke=23.7nM). While the 6-substituted analogs were generally inactive, several 6-amino compounds bearing ester groups showed reasonable potency (26a, Ke=427nM). Further, we show evidence that suggests several compounds initially displaying insurmountable antagonism at the OX1 receptor are competitive antagonists with slow dissociation rates.

Synthesis of atropisomeric chiral MeOBIPHEP analogues via Pd-catalyzed P–C coupling — applications to asymmetric Rh-catalyzed C–C bond formations in water

The preparation and catalytic applications of water-soluble MeOBIPHEP-based atropisomeric chiral congener ligands are described. The optimization of the catalytic system to promote the key P–C coupling revealed the superiority of palladium catalysts versus nickel or copper. Spectroscopic studies of the Pd-catalyzed reaction medium showed the presence of phosphorylated intermediates. The asymmetric Rh-catalyzed 1,4-addition of boronic acids to enones in water was described in the presence of water-soluble MeOBIPHEP derivatives. The 4-CO2Na-, 3-CO2Na- and 3,5-(CO2Na)2-substituted MeOBIPHEP analogues showed high and complementary reactivities and enantioselectivities, considering either the enone or the boronic acid.

Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.

A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.

Synthesis and anticancer activity of thiosubstituted purines.

New thiopurines with the propargylthio, pyrrolidinobutynylthio, sulfenamide, and sulfonamide groups in the pyrimidine ring were synthesized. The anticancer activity of these compounds and previously obtained 2- or 6-substituted azathioprine analogs and dialkylaminoalkylthiopurines were tested in vitro against three cell lines: glioblastoma SNB-19, melanoma C-32, and human ductal breast epithelial tumor T47D. 2-Chloro-7-methyl-6-pyrrolidinobutynylthiopurine (5b) was the most potent compound against SBN-19 and C-32 cell lines with the activity similar to cisplatin (EC50 = 5.00 and 7.58 μg/ml, respectively). The dialkylaminoalkylthio derivatives (4b, 4c, 4e, and 4f) showed good activity against SBN-19 cell line (EC50 < 10 μg/ml). The azathioprine analogs (2a, 2b, and 3a) were more active than azathioprine against SBN-19 and C-32 cell lines. The sulfenamide and sulfonamide derivatives of purine were very weak active against tested cell lines. All studied thiopurines were less toxic than cisplatin.Electronic supplementary materialThe online version of this article (doi:10.1007/s00044-015-1364-2) contains supplementary material, which is available to authorized users.

QSAR Analysis of 3- and 4-substituted 7-hydroxycoumarins as Novel 17?-HSD3 Inhibitors

A series of 3- and 4-substituted 7-hydroxycoumarins analogues were analyzed for structure–activity relationship using sphere exclusion algorithm method. The QSAR studies were analyzed and the structural features contributing to the enhancement of activity were identified. 2D-QSAR statistically significant model with coefficient of determination (r2) of 0.8291 and cross validated correlation coefficient (q2) of 0.7455. The 2D-QSAR results revealed that that the presence of chloro or fluoro substituents would increase the 17β-HSD3 inhibitory activity and presence of bulky electron withdrawing groups at R1 and R2 position of ring would increases the 17β-HSD3 inhibitory activity. Based on the results obtained from these analysis some compounds were designed which show enhancement in activity compared to the parent compound.

Iodine Monochloride Facilitated Deglycosylation, Anomerization, and Isomerization of 3-Substituted Thymidine Analogues

The reaction of thymidine, 3-mono-, and 3,3′,5′-trialkylsubstitued thymidine analogues with iodine monochloride (ICl) was investigated. Treatment with ICl resulted in rapid deglycosylation, anomerization, and isomerization of thymidine and 3-substituted thymidine analogues under various reaction conditions leading to the formation of the nucleobases as the major products accompanied by minor formation of α-furanosidic-, α-pyranosidic-, and β-pyranosidic nucleosides. On the other hand, 3,3′,5′-trisubstitued thymidine analogues were only deglycosylated and anomerized. These results are similar to those observed for the acidic hydrolysis of the glycoside bond in nucleosides, but were presumably caused by the Lewis acid character of an iodine electrophile.

5-(Piperidin-4-yl)-3-hydroxypyrazole: A novel scaffold for probing the orthosteric γ-aminobutyric acid type A receptor binding site.

A series of bioisosteric N1- and N2 -substituted 5-(piperidin-4-yl)-3-hydroxypyrazole analogues of the partial GABAA R agonists 4-PIOL and 4-PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3-hydroxypyrazole analogue of 4-PIOL (2 a; IC50 ∼300 μM) is a weak antagonist at the α1 β2 γ2 GABAA R, whereas substituting the N1- or N2- position with alkyl or aryl substituents resulted in antagonists with binding affinities in the high nanomolar to low micromolar range at native rat GABAA Rs. Docking studies using a α1 β2 γ2 GABAA R homology model along with the obtained SAR indicate that the N1 -substituted analogues of 4-PIOL and 4-PHP, 2 a-k, and previously reported 3-substituted 4-PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N2 -substituted analogues of 4-PIOL and 4-PHP, 3 b-k, are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold.

Competitive antagonism of insect GABA receptors by 4-substituted 5-(4-piperidyl)-3-isothiazolols

γ-Aminobutyric acid (GABA) receptors are important targets of parasiticides/insecticides. Several 4-substituted analogs of the partial GABAA receptor agonist 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) were synthesized and examined for their antagonism of insect GABA receptors expressed in Drosophila S2 cells or Xenopus oocytes. Thio-4-PIOL showed weak antagonism of three insect GABA receptors. The antagonistic activity of Thio-4-PIOL was enhanced by introducing bicyclic aromatic substituents into the 4-position of the isothiazole ring. The 2-naphthyl and the 3-biphenylyl analogs displayed antagonist potencies with half maximal inhibitory concentrations in the low micromolar range. The 2-naphthyl analog induced a parallel rightward shift of the GABA concentration–response curve, suggesting competitive antagonism by these analogs. Both compounds exhibited weak insecticidal activities against houseflies. Thus, the orthosteric site of insect GABA receptors might be a potential target site of insecticides.

ChemInform Abstract: Synthesis of Substituted Tryptanthrins via Oxidation of Isatin and Its Derivatives.

Oxidation of isatin and its 5-substituted analogs with potassium permanganate in anhydrous acetonitrile gave indolo[2,1-b]quinazoline-6,12-dione (tryptanthrin) and its 2,8-dimethyl-, 2,8-dibromo-, and 2,8-diiodo derivatives. Oxidative coupling of 5,7-dichloroisatin with isatin under analogous conditions afforded 2,4-dichloroindolo[2,1-b]quinazoline-6,12-dione, while 1,4-dichloroindolo[2,1-b]quinazoline-6,12-dione and 1,4-dichloro-8-methylindolo[2,1-b]quinazoline-6,12-dione were obtained by oxidative coupling of 4,7-dichloroisatin with isatin and 5-methylisatin, respectively.

Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ0).

A convergent and stereoselective synthesis of chiral cyclopentyl- and cyclohexylamine derivatives of nucleoside Q precursor (PreQ0) has been accomplished. This synthetic route allows for an efficient preparation of 4-substituted analogues with interesting three-dimensional character, including chiral cyclopentane-1,2-diol and -1,2,3-triol derivatives. This unusual substitution pattern provides a useful starting point for the discovery of novel bioactive molecules.

Synthesis and biological evaluation of some novel 1-substituted fentanyl analogs in Swiss albino mice.

Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a potent opioid analgesic agent, but a has narrow therapeutic index. We reported earlier on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs (1–4) in mice. Here we report the synthesis and biological evaluation of four additional analogs, viz. N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6), isopropyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (7) and t-butyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (8). The median lethal dose (LD50) determined by intravenous, intraperitoneal and oral routes suggests these analogs to be comparatively less toxic than fentanyl. On the basis of observational assessment on spontaneous activities of the central, peripheral, and autonomic nervous systems, all the analogs were found to be similar to fentanyl. Naloxone hydrochloride abolished the neurotoxic effects of these analogs, thereby ascertaining their opioid receptor-mediated effects. All the analogs displayed significant analgesic effects, measured by formalin-induced hind paw licking and tail immersion tests at their respective median effective dose (ED50). They also exhibited 8–12 fold increase in therapeutic index over fentanyl. However, 5 and 6 alone produced lower ED50 (20.5 and 21.0 µg/kg, respectively) and higher potency ratio (1.37 and 1.33, respectively) compared to fentanyl. They could thus be considered for further studies on pain management.

An inhibitor-driven study for enhancing the selectivity of indirubin derivatives towards leishmanial Glycogen Synthase Kinase-3 over leishmanial cdc2-related protein kinase 3.

BackgroundIn search of new antiparasitic agents for overcoming the limitations of current leishmaniasis chemotherapy, we have previously shown that 6-bromoindirubin-3'-oxime (6BIO) and several other 6-substituted analogues of indirubin, a naturally occurring bis-indole present in mollusks and plants, displayed reverse selectivity from the respective mammalian kinases, targeting more potently the leishmanial Cyclin-Dependent Kinase-1 (CDK1) homologue [cdc2-related protein kinase 3 (LCRK3)] over leishmanial Glycogen Synthase Kinase-3 (LGSK-3). This reversal of selectivity in Leishmania parasites compared to mammalian cells makes the design of specific indirubin-based LGSK-3 inhibitors difficult. In this context, the identification of compounds bearing specific substitutions that shift indirubin inhibition towards LGSK-3, previously found to be a potential drug target, over LCRK3 is imperative for antileishmanial targeted drug discovery.MethodsA new in-house indirubin library, composed of 35 compounds, initially designed to target mammalian kinases (CDKs, GSK-3), was tested against Leishmania donovani promastigotes and intracellular amastigotes using the Alamar blue assay. Indirubins with antileishmanial activity were tested against LGSK-3 and LCRK3 kinases, purified from homologous expression systems. Flow cytometry (FACS) was used to measure the DNA content for cell-cycle analysis and the mode of cell death. Comparative structural analysis of the involved kinases was then performed using the Szmap algorithm.ResultsWe have identified 7 new indirubin analogues that are selective inhibitors of LGSK-3 over LCRK3. These new inhibitors were also found to display potent antileishmanial activity with GI50 values of <1.5 μΜ. Surprisingly, all the compounds that displayed enhanced selectivity towards LGSK-3, were 6BIO analogues bearing an additional 3'-bulky amino substitution, namely a piperazine or pyrrolidine ring. A comparative structural analysis of the two aforementioned leishmanial kinases was subsequently undertaken to explain and rationalize the selectivity trend determined by the in vitro binding assays. Interestingly, the latter analysis showed that selectivity could be correlated with differences in kinase solvation thermo dynamics induced by minor sequence variations of the otherwise highly similar ATP binding pockets.ConclusionsIn conclusion, 3'-bulky amino substituted 6-BIO derivatives, which demonstrate enhanced specificity towards LGSK-3, represent a new scaffold for targeted drug development to treat leishmaniasis.