Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2

Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT_1A receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT_1A receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT_1A receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with –OCH₃ or –F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT_1A receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity.     

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. part 3

A number of 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine with 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole or 2-methyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole residues were synthesized for further investigation of SAR in a group of pyrido[1,2-c]pyrimidine derivatives with dual 5-HT_1A/SERT activity. Compounds 8a-8p were found to be potent ligands for both 5-HT_1A and SERT with K_i ranging from 28,3 to 642 nM and 42,4 nM-1,8 μM, respectively. Moreover compounds 8a, 8b, 8c, 8d, 8e and 8g were found to be selective agonists, while 8i as an antagonist of 5-HT_1A presynaptic receptors in the inducible hypothermia test in mice.     

Design and synthesis of 2-phenylimidazo[1,2-a]pyridines as a novel class of melatonin receptor ligands

A novel class of imidazo[1,2-a]pyridines as melatonin receptor ligands is designed and synthesized. The affinities of 3-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-N-methyl-propionamide 8, N-[2-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-ethyl]-acetamide 13 and N-(1-hydroxy-3-(5-methoxy-2-phenyl-1H-indol-3-yl)propan-2-yl)acetamide 18 are evaluated for binding on melatonin receptors. Compound 8 present good selectivity for MT₂ over MT₁ (MT₁/MT₂ = 19) and compound 13 have good affinities for both MT₁ (Ki :28 nM) and MT₂ (Ki : 8 nM).     

Synthesis and preliminary pharmacological evaluation of imidazo[2,1-f]purine-2,4-dione derivatives

A series of N-8-arylpiperazinylpropyl derivatives of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2–10) and amide derivatives of 1,3-dimethyl-6,7-dihydroimidazo[2,1-f]purine-2,4-(1H,3H)-dione-7-carboxylic acid (11–13) were synthesized. Compounds (2–10) evaluated in vitro were potent 5-HT_1A receptor ligands. Preclinical studies indicated that 8-[3-(N4-phenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2) exerts anxiolytic-like activity in the four-plate test in mice; however its effect was weaker, than that produced by Diazepam. This compound and 8-[3-(N4-2′-metoxyphenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (3) behaved like antidepressants in the forced swimming test in mice; and their activity in that model was comparable with the effect of Imipramine. The obtained results suggested that the long-chain arylpiperazines (LCAPs) linked to tricyclic derivatives of the theophylline remain a worthy of future research for obtaining new derivatives with potential anxiolytic/antidepressant activity.     

Synthesis and anticonvulsant activity of some new thiazolo[3,2-a][1,3]diazepine, benzo[d]thiazolo[5,2-a][12,6]diazepine and benzo[d]oxazolo[5,2-a][12,6]diazepine analogues

A new series of 6,7-dihydro-thiazolo[3,2-a][1,3]diazepines (9–12), benzo[d]thiazolo[5,2-a][12,6]diazepines (19–21) and benzo[d]oxazolo[5,2-a][12,6]diazepine (24) analogues were synthesized and evaluated for their anticonvulsant activity. Compounds (E)-2-bromo-6,7-dihydro-thiazolo[3,2-a][1,3]diazepine-8(5H)-thione (12), 3-chloro-benzo[d]thiazolo[5,2-a][12,6]diazepin-10-one (20), and 4-chloro-benzo[d]oxazolo[5,2-a][12,6] diazepin-10-one (24) showed 100% protection against PTZ- and bicuculline-induced seizures; 70%, 33%, 70% protection against MES-induced tonic extension; and 70%, 66%, 100% protection against picrotoxin-induced convulsions, respectively. Compounds 12, 20, and 24 proved to act as GABA_A receptor agonists, with ED₅₀ values of 252, 380, 251 mg/kg; TD₅₀ values of 398, 417, 355 mg/kg; PI values of 1.58, 1.09, 1.41; LD₅₀ values of 380, 617, 537 mg/kg and TI values of 1.51, 1.62, 2.14, respectively.     

Synthesis and inhibition study of monoamine oxidase, indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by 3,8-substituted 5H-indeno[1,2-c]pyridazin-5-one derivatives

Previous studies on 5H-indeno[1,2-c]pyridazin-5-one derivatives as inhibitors of MAO-B revealed that it was possible to increase the MAO-B inhibitory potency of 5H-indeno[1,2-c]pyridazin-5-ones by substituting the central heterocycle in the 3-position or C-8 with lipophilic groups which occupy the substrate cavity or the entrance of the binding site, respectively. Here, four new 5H-indeno[1,2-c]pyridazin-5-one derivatives containing lipophilic groups at both positions were synthesized and their inhibitory potency against human monoamine oxidase A and B were evaluated. Selectivity of these compounds against IDO and TDO, two enzymes sharing substrate similarity with MAO and involved in the serotonergic and kynurenine pathways was also studied. All compounds showed higher activity and selectivity against MAO-B, the most effective one being 3-methyl-8-meta-chlorobenzyloxy-5H-indeno[1,2-c]pyridazin-5-one (9a) which was shown to be a competitive inhibitor with a K_i value of 0.11 μM. Replacing the methyl group in the 3-position with a meta–CF₃–phenyl group (7a, 7b and 7c) abolished the inhibitory potency against MAO-B. Indeed, the substitution of the 5H-indeno[1,2-c]pyridazin-5-one core in the 3-position dramatically influences the MAO-inhibiting properties of these compounds. Molecular docking studies of 9a within MAO-B suggest that the 5H-indeno[1,2-c]pyridazin-5-one scaffold is well stabilized into the substrate cavity with the meta-chlorobenzyloxy side chain extending towards a rather hydrophobic pocket at the entrance cavity.     

Synthesis of novel bioactive derivatives of 3-(4-chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidine-4(3H)-ones

A series of triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones (12a–n) were synthesized and evaluated for CNS depressant, skeletal muscle relaxant and anticonvulsant activities by photoactometer, Rotarod and pentylenetetrazole induced the convulsions method respectively in Swiss albino mice. Diazepam was used as standard drug. The five derivatives 12b, 12c, 12d, 12i and 12m showed the CNS depressant and skeletal muscle relaxant activities comparable to those of diazepam at a dose of 5 mg/kg. These derivatives also exhibited good activity when tested for anticonvulsant activity in mice at different dose levels. The ED₅₀ values for these derivatives are in the range of 4.40–9.33 mg/kg.     

Pyrroloquinolones and pyrazoloquinolones as potential antibacterial agents. Synthesis and antibacterial activity

Diethyl 1-cyclopropyl-5,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3,6-dicarboxylate 4 as a key-intermediate was synthesized via the Dieckmann reaction. The reaction of 4 with nucleophiles proceeded regioselectively at C-5. Facile cyclization between the C-5 and C-6 side chains of the resulting products gave novel pyrroloquinolones 10 and 12 and pyrazoloquinolones 15. They were converted into a series of cyclic amino-substituted pyrroloquinolones 17–21 and pyrazoloquinolones 22–24, and their in vitro antibacterial activities were tested. 1H-Pyrrolo[2,3-f]quinolone 17a and 2H-pyrrolo[3,4-f]quinolone 21a exhibited a potent in vitro antibacterial activity.     

Design, synthesis and antimycobacterial activity of some novel imidazo[1,2-c]pyrimidines

Tuberculosis, due to its relentless nature, is now a major public health threat. The concomitant resurgence of TB with the MDR- or XDR-TB and HIV/AIDS pandemic has exposed the frailties of the current drug armatorium. Based on isosteric replacement and good 3D structural similarity between PA-824, a novel antimycobacterial agent undergoing clinical trials, and imidazo[1,2-c]pyrimidines, we have designed novel imidazo[1,2-c]pyrimidines. The designed molecules were synthesized by nucleophilic displacement of chloro group of various substituted 4-chloropyrimidines by ethanolamine followed by cyclisation of these 4-(2-hydroxyethyl)aminopyrimidines to imidazo[1,2-c]pyrimidines in good yield. All the compounds were screened for their antimycobacterial activity on Mycobacterium tuberculosis H37Rv strain by 1% proportion method. Some of the synthesized compounds exhibited potent antimycobacterial activity with MIC values in the range of 2–20 μg/mL.     

Synthesis and in vitro antitumour activity evaluation of 1-aryl-1H,3H-thiazolo[4,3-b]quinazolines

A series of 1H,3H-thiazolo[4,3-b]quinazolines (2a–i) were synthesized and evaluated for their in vitro antitumour activity against ca. 60 human tumour cell lines. They exhibited moderate (2c, 2d, 2f and 2g) to strong (2a, 2b, 2e, 2h and 2i) cell-growth inhibition at a concentration of 10⁻⁴ M, but weak activity at lower concentrations. Only 1-(2,6-dichlorophenyl)-1H,3H-thiazolo[4,3-b]quinazoline (2h) possesses a significant growth inhibitory activity on 22 cell lines at a concentration of 10⁻⁵ M.     

Synthesis, in vitro antimicrobial and in vivo antitumor evaluation of novel pyrimidoquinolines and its nucleoside derivatives

Seven series of pyrimidoquinoline derivatives have been synthesized, tetrazolo[4′,3′:-1,2]pyrimido[4,5-b]quinoline (3), 2-aminopyrimido[4,5-b]quinoline (4), triazolo[4′,3′:1,2]-pyrimidoquinoline (5a,b, 10), imidazolo[3′,2′:1,2]pyrimido[4,5-b]-quinoline (8a,b), 6-chloro-2-methylthiopyrimido[4,5-b]quinoline (12), acetylated nucleosides (16, 17a,b) and deacetylated nucleosides (18, 19a,b). Some of the novel pyrimidoquinoline derivatives possess highly activity toward the bacteria and fungi species. The new quinolines derivatives were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute (NCI). Most of them had excellent growth inhibition activity, having LD₅₀ values in the low micromolar to nanomolar concentration range.     

Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones

Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1-33) were evaluated for their affinity to rat adenosine A₁ and A_2A receptors. Selected compounds were additionally investigated for affinity to the human A₁, A_2A, A_2B and A₃ receptor subtypes. The results of the radioligand binding assays at adenosine A₁ and A_2A receptors showed that most of the compounds exhibited adenosine A_2A receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A_2A affinity. The most potent A_2A ligands of the present series were compounds 6 (K_i 0.33 μM rat A_2A, 0.31 μM human A_2A), 8 (K_i 0.98 μM rat A_2A, 0.42 μM human A_2A) and 15 (K_i 0.24 μM rat A_2A, 0.61 μM human A_2A) with the latter one showing high A_2A selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A_2A receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power (q² = 0.88) for A_2A AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure-activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A_2A antagonists with good water-solubility.     

Design, synthesis and in vitro evaluation of bridgehead fluoromethyl analogs of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) for the 5-HT(1A) receptor

Fluorinated analogs that are related to the 5-hydroxytryptamine (5-HT_1A) antagonist, N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635), have been synthesized and their binding affinity for the 5-HT_1A receptor and other neurotransmitter receptors (adrenoceptors, sigma receptors, and dopamine receptors), and serotonin transporters was examined in vitro. These ligands were designed to provide a possible potential positron emission tomography (PET) ligand with high metabolic stability. To this end, the cyclohexyl moiety in WAY-100635 and in O-desmethyl WAY-100635 was replaced by a bridge-fused ring (BFR) such as adamantyl, cubyl, bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptyl to reduce the metabolic rate of the amide bond hydrolysis, while a fluoromethyl group was introduced on the other bridgehead of the BFR to prevent defluorination by HF elimination. All synthesized analogs displayed high affinity in the (sub)nanomolar range for the 5-HT_1A receptor, comparable to WAY-100635. In addition, 6b, 6c and 6d were reasonably selective to the 5-HT_1A receptor over the above mentioned receptors. In human hepatocytes, 6b showed a suitable metabolic stability.In conclusion, the obtained data provides a promising starting point for the synthesis of the corresponding ¹⁸F-labeled PET analogs.     

Single step synthesis of new fused pyrimidine derivatives and their evaluation as potent Aurora-A kinase inhibitors

A simple, facile, efficient and one pot three-component procedure for the synthesis of pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and pyrimido[1,2-a]benzimidazoles ring systems incorporating phenylsulfonyl moiety was developed via the reaction of 1-aryl-2-(phenylsulfonyl)ethanone derivatives 1a-d with the appropriate heterocyclic amine and triethyl orthoformate and evaluated as Aurora-A kinase inhibitors. The cytotoxic activity of the newly synthesized compounds against HST116 colon tumor cell line was investigated. 2,7-Diphenyl-6-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidine (4b) and its p-methoxy analogue 4c were found to be equipotent to Doxorubicin as a reference drug. Molecular modeling study was carried out in order to rationalize the in vitro anti-tumor results.     

Synthesis and antimycobacterial evaluation of 3a,4-dihydro-3H-indeno [1,2-c] pyrazole-2-carboxamide analogues

In the present investigation, a series of 3a,4-dihydro-3H-indeno [1,2-c] pyrazole-2-carboxamide analogues were synthesized and were evaluated for antitubercular activity by two fold serial dilution technique. All the newly synthesized compounds showed low to good inhibitory activities against Mycobacterium tuberculosis H₃₇Rv and multi-drug resistant M. tuberculosis (MDR-TB). 3-(4-fluorophenyl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno [1,2-c] pyrazole-2-carboxamide (4c) was found to be the most promising compound active against M. tuberculosis, H₃₇Rv and MDR-TB with minimum inhibitory concentrations 0.83 μM and 3.32 μM respectively.     

Pyrimido[5,4-b]benzofuran and pyrimido[5,4-b]benzothiophene derivatives Ligands for α1-and 5HT1A-receptors

A number of 3-phenylpiperazinylethyl pyrimido[5,4-b]benzofuran-2,4-dione and pyrimido[5,4-b]benzothiophene-2,4-dione derivatives 5–15 were designed as bioisosters of the previously reported pyrimido[5,4-b]indole-2,4-diones and synthesized starting from the 3-amino-2-carboxybenzofuran and benzothiophene ethyl and methyl esters respectively. They were evaluated for their in vitroα₁-adrenoceptor and 5HT_1A-receptor affinities by radioligand receptor binding assays. All target compounds showed good to excellent affinities for the α₁-adrenoceptor with K_i values in the subnanomolar range. Some compounds were also good ligands for the 5HT_1A-receptor with K_i values in the nanomolar range. 3-[2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl]-1-methyl pyrimido[5,4-b]benzothiophen-2,4-dione 15 was the most active derivative in displacing [³H]-8-OH-DPAT from rat hippocampal membranes. There is evidence suggesting that the N₁ methyl group of the tricyclic moiety of the title compounds is probably able to undergo a Van der Waals interaction at the 5HT_1A-receptor binding site but not at the α₁-adrenoceptor active site.     

Structure-activity relationship studies of CNS agents. Part 29. N-Methylpiperazino-substituted derivatives of quinazoline, phthalazine and quinoline as novel α1, 5-HT1A and 5-HT2A receptor ligands

New N-methylpiperazino-substituted quinazolines 8 and 9, phthalazine 13, and quinoline 19 have been synthesized. The receptor binding profiles (α₁, 5-HT_1A, 5-HT_2A) of these compounds and their analogs (7–22) have been determined. It has been demonstrated that orientation of a local dipole moment of the heteroaromatic ring system affects both the α₁ and 5-HT_2A affinity of the investigated class of ligands. Distortion of the coplanar unfused heteroaromatic ring system results in a decreased 5-HT_2A affinity. 4-(4-Methylpiperazino)-2-(2-thienyl)quinoline 18 is the most active and selective α₁ ligand (K_i = 4.9 nM) with a much lower affinity for 5-HT_1A (K_i = 3420 nM) and 5-HT_2A (K_i = 211 nM) receptors.     

Antimalarial activity of imidazo[2,1-a]isoindol-5-ol derivatives and related compounds

The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evaluation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the incorporation of an additional fused ring, were analyzed. Several compounds showed significant antimalarial activity in vitro with IC₅₀ values as low as 60 nM and a certain efficacy in vivo by reducing parasitemia in Plasmodium berghei mouse models.     

5H-[1,2,4]Oxadiazolo[5,4-d][1,5]benzothiazepines as anticonvulsant agents in DBA/2 mice

A series of 3a,4-dihydro-5H-[1,2,4]oxadiazolo[5,4-d][1,5]benzothiazepines have been synthesized by 1,3-dipolar cycloaddition reaction of benzonitriloxide to the CN double bond of 1,5-benzothiazepine derivatives, and the stereochemical features of compounds obtained have been determined by NMR spectroscopy. The results of evaluation of their activity in preventing seizures induced by audiogenic stimulation in DBA/2 mice are also reported and discussed. The 5-(4-bromophenyl)-1,3-diphenyl derivative 3b, the most active compound of the series, is over 20 times more active than the parent benzothiazepine 1b and shows an activity comparable to clobazam and better than desmethylclobazam.     

Synthesis and antifungal activities of novel 5,6-dihydro-indolo[1,2-a]quinoxaline derivatives

A series of new 5,6-dihydro-indolo[1,2-a]quinoxaline derivatives has been prepared in moderate to excellent yields from 2-(indol-1-yl)phenylamines with aromatic aldehydes by an efficient and economical iron-catalyzed Pictet-Spengler reaction. Meanwhile, as compared with hymexazol, a commercially available agricultural fungicide at the concentration of 50 μg/mL, some 5,6-dihydro-indolo[1,2-a]quinoxalines exhibited promising antifungal activities in vitro against the phytopathogenic fungi, and might be considered as novel promising lead candidates for further design and synthesis of agricultural fungicides.