Synthesis and structural investigation of some pyrimido[5,4-c]quinolin-4(3H)-one derivatives with a long-chain arylpiperazine moiety as potent 5-HT(1A/2A) and 5-HT(7) receptor ligands

A series of new pyrimido[5,4-c]quinolin-4(3H)-ones with variable length of the spacer between amide and 4-arylpiperazine moiety were prepared to further explore the role of a terminal portion in the serotonergic activity. The majority of compounds demonstrated high in vitro affinity for 5-HT_1A receptor, and moderate-to-low affinity for 5-HT_2A and 5-HT₇ receptors. X-ray analysis, two-dimensional NMR, conformational studies and docking into the 5-HT_1A receptor model were conducted to investigate conformational preferences of selected 5-HT_1A receptor ligands in different environments. The extended conformation of tetramethylene derivatives was found in a solid state, in DMSO (for a protonated form) and as a global energy minimum during conformational analysis in simulated water environment. Ligand geometry in top-scored complexes, obtained by docking to a set of 100 receptor models, were either fully extended or with central spacer torsion in synclinal conformation.     

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

A series of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine containing the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy derivative were synthesized. They were characterized (i) in vitro by binding to 5-HT(1A) receptors and 5-HT transporter proteins in rat brain cortex membranes and (ii) in vivo in the mouse by induced hypothermia and forced swimming models for antagonist/agonist activity against the 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors, respectively. Structure activity relationship evaluation indicated that the presence of the 3-(4-piperidyl)-1H-indole residue and ortho- or para-substituents with -F or -CH(3) groups in the aryl ring as well as an unsubstituted aryl in the 4-aryl-pyrido[1,2-c]pyrimidine moiety promoted low K(i) values for both receptors. In contrast, the presence of a 5-methoxy-3-(4-piperidyl)-1H-indole residue as well as -Cl or -OCH(3) substituents at the para position markedly reduced the receptor 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.     

Synthesis and preliminary pharmacological results on new naphthalene derivatives as 5-HT(4) receptor ligands

The indole derivative GR 113808 is currently used as the reference ligand for labelling the 5-HT(4) serotoninergic receptors. Previous works in our laboratories established the bioisosteric equivalency of the indole heterocycle and naphthalene in a series of melatonin receptor ligands. Based on this knowledge we designed new analogues of GR 113808 by introducing two bioisosteric modifications: firstly, the indole ring was replaced by a naphthalene one and secondly, the ester linkage was replaced by an amide group. Compound 8 emerged within this novel series as it displayed high and selective affinity at 5-HT(4) receptors (Ki 5-HT(4) = 6 nM, Ki 5-HT(3) = 100 nM, Ki values at other 5-HT receptors were higher than 1000 nM). Compound 8 is currently undergoing further pharmacological evaluation.     

Synthesis, anticonvulsant activity and 5-HT1A, 5-HT2A receptor affinity of new N-[(4-arylpiperazin-1-yl)-alkyl] derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione

The synthesis, physicochemical and pharmacological properties of new N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.4]nonane- (8a-c, 10a-d) and [4.5]decane-1,3-dione (9a-c, 11a-d) derivatives were described. The antiepileptic effects of those compounds were examined by a maximal electroshock (MES) and a pentylenetetrazole (sc. PTZ) tests, and their neurotoxicity was determined using a rota-rod test. Compounds 8c, 9c, 10c, d, 11c, d with a CF(3) group at the 3-position of the 4-arylpiperazine fragment exhibited anti-seizure properties in the MES model; in contrast, their 2-CH(3) and 2-OCH(3) analogues were inactive in both the tests used. Moreover, since the investigated compounds belong to the class of long-chain arylpiperazines, their serotonin 5-HT(1A) and 5-HT(2A) receptor affinity was determined. The relationship between the length of alkylene spacer and 5-HT(1A)/5-HT(2A) receptor activity was observed. Compounds with an ethylene and a propylene bridge (10a-d and 11a-d) were 3-80-fold more potent (K(i) ranged from 3.1 to 94 nM for 5-HT(1A) and 32-465 nM for 5-HT(2A)) than their methylene analogues (8a-c and 9a-c; K(i) ranged from 81 to 370 nM for 5-HT(1A) and 126-1370 nM for 5-HT(2A)). The highest 5-HT(1A) receptor affinity was displayed by 2-OCH(3) and 3-CF(3) phenyl derivatives (10b, 11b: K(i)=6.8 and 5.7 nM, respectively, and 10c, 11c: K(i)=6.0 and 3.1 nM, respectively), while in the case of 5-HT(2A) receptor the highest affinity was observed for the 3-CF(3) phenyl derivatives 10c, d, 11c, d (K(i) ranged from 32 to 86 nM).     

Antifungal agents. Part 4: Synthesis and antifungal activities of novel indole[1,2-c]-1,2,4-benzotriazine derivatives against phytopathogenic fungi in vitro

A series of novel indole[1,2-c]-1,2,4-benzotriazine derivatives were obtained by a modified Sandmeyer reaction in the presence of tert-butylnitrite (t-BuONO). As compared with hymexazol, a commercially available agricultural fungicide, at the concentration of 50 μg/mL, two indole[1,2-c]-1,2,4-benzotriazines, 5h and 5k, exhibited the more promising and pronounced antifungal activities in vitro against five phytopathogenic fungi. It clearly demonstrated that introduction of appropriate substituents on the indolyl ring of indole[1,2-c]-1,2,4-benzotriazine (5a) would lead to the more potent derivatives.     

Synthesis and antimicrobial activity of some new 4-hetarylpyrazole and furo[2,3-c]pyrazole derivatives

In continuation of our efforts to find a new class of antimicrobial agents, a series of 4-hetarylpyrazoles and furo[2,3-c]pyrazoles were prepared via the reaction of 2-chloro-1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone (1) with an appropriate nucleophilic reagents. These compounds were screened for their antibacterial activity against Gram-positive bacteria (Bacillus subtilis and Bacillus thuringiensis), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and antifungal activity against Fusarium oxysporum and Botrytis fabae. Among the synthesized compounds, 1-(5-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-yl)-2-methylfuran-3-yl)ethanone (12) showed equal activity with chloramphenicol against B. subtilis (MIC 3.125 μg/mL), while its activity was 50% lower than of chloramphenicol against B. thuringiensis. N-[(4Z)-3-Methyl-1-phenyl-1H-furo[2,3-c]pyrazol-4(5H)-ylidene]-1H-benzimidazol-2-amine (7) and 2-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-4H-furo[3,2-c]chromen-4-one (13) were found to exhibit the most potent in vitro antifungal activity with MICs (6.25 μg/mL) against B. fabae and F. oxysporum.     

Synthesis, binding properties and receptor docking of 4-halo-6-[2-(4-arylpiperazin-1-yl)ethyl]-1H-benzimidazoles, mixed ligands of D2 and 5-HT1A receptors

In this publication we are describing synthesis, binding properties, and receptor docking of 4-halo-6-[2-(4-arylpiperazin-1-yl)ethyl]-1H-benzimidazoles, a new compounds with potential antipsychotics properties. Affinity towards the dopamine D(1)-like and D(2)-like, and serotonin 5-HT(1A) receptors was evaluated using the radioligand binding assays. All compounds tested had affinity for the D(2)-like and 5-HT(1A) receptors, but were inactive towards the D(1)-like receptor. Halogenated 6-[2-(4-arylpiperazin-1-yl)ethyl]-1H-benzimidazoles showed higher affinity compared to their nonhalogenated congeners. In silico docking analysis of selected ligands was performed in order to explain the results of binding assays. Our analysis suggests that stabilizing interactions between the halogen atom at the benzimidazole ring and the Ser-122 of the D(2)-like and Trp-358 of the 5-HT(1A) receptor. Energy contributions for these interactions were calculated using the ab initio method.     

Post Groebke-Blackburn multicomponent protocol: synthesis of new polyfunctional imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives as potential antimicrobial agents

New antimicrobial agents [imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine] have been synthesized. Their antimicrobial activities were conducted against various Gram-positive and Gram-negative bacteria including Staphylococcus aureus. Compounds 5d, 7a, 10a, 11a and 12a proved to efficiently inhibit the growth of all the Gram-positive and Gram-negative strains investigated. Results of this study showed that the nature of the substituents on the armed phenyl groups determined the extent of the activity of the fused imidazopyridine and/or imidazopyrimidine derivatives. Preliminary structure-activity observations revealed that groups with positive sigma and positive bi values (e.g. 5d, 6c, 12a, 12d) were significantly more active compared to other bioisosteres (e.g. 5b). Furthermore, increasing the molar refractivity of the substitution pattern (e.g. 5b, 6b and 6d) sharply decreased the antibacterial activity.     

Synthesis and antigenotoxic activity of some naphtho[2,1-b]pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives

In this study, some pyranotriazolopyrimidine derivatives were synthesised by reacting ethoxymethyleneamino derivatives with hydrazides. Their structures were elucidated by IR, (1)H NMR, and (13)C NMR spectroscopic data and elemental analyses. Antigenotoxic activity of the obtained compounds was tested in Escherichia coli PQ37 by using the SOS chromotest.     

Antinociceptive activity of new imidazolidine carbonyl derivatives. Part 4. Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2H,8H-6,7-dihydroimidazo[2,1-c] [1,2,4]triazines

Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2H,8H-6,7-dihydroimidazo[2,1-c] [1,2,4]triazines (A) are presented. The title compounds were obtained from 1-aryl-2-hydrazinoimidazolines (1) by cyclization reaction with ethyl oxalate (2). They were tested for pharmacological activity in behavioral animal tests (A1, A3, A5, A6, A8, A9). With relatively low acute toxicity (LD50 in range from 1100 to over 2000 mg kg(-1), intraperitoneally, i.p.), some of them exhibited significant antinociceptive activity as the result of the 'writhing' test indicated. Especially strong antinociception for compound A8 and significant for A6 was observed in doses of 12.5-200 mg (0.00625-0.1 LD50) and 37.5-150 mg (0.025-0.1 LD50), respectively. Reversion of the antinociception for A1 and A8 produced in the 'writhing' test by 5 mg kg(-1) dose of naloxon can suggest an opioid-like mechanism of their analgesic activity. Additionally, compound A9 reduced number of the "head twitch" episodes after 5-hydroxytryptophan (5-HTP) administration with no antinociceptive effect at all and compound A3 showed significant protection in the pentylentetrazol-induced seizure model. Differences observed in the activity spectrum between A8 and A9 derivatives can be explained on the base of difference in the amido-imido tautomeric equilibrium observed between these two compounds.     

Synthesis and anticonvulsant activity of novel 2,6-diketopiperazine derivatives. Part 1: perhydropyrrole[1,2-a]pyrazines

A number of novel pyrrole[1,2-a]pyrazine derivatives were synthesized and evaluated in in vivo animal models of epilepsy. Among them, several compounds displayed promising seizure protection in the maximal electroshock seizure (MES), subcutaneous metrazol seizure (scMET), 6 Hz and pilocarpine-induced status prevention (PISP) tests, with ED₅₀ values comparable to the reference anticonvulsant drugs (AEDs). A critical influence of the stereochemistry and conformational preferences of the pyrrole[1,2-a]pyrazine core on in vivo pharmacological activity was observed. The mechanism of the anticonvulsant action of the agents synthesized is most probably not via inhibition of the voltage-dependent sodium (Na⁺) currents.     

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Part 1. Synthesis and pharmacological activity of chain derivatives of 1-aryl-2-iminoimidazolidine containing urea moiety.

The synthesis and physicochemical properties of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine are presented. Isomeric 1-(1-arylimidazolidine-2-ylidene)-3-arylureas (series A) and 1-aryl-2-imine-3-arylaminocarbonylimidazolidines (series B) were obtained after the condensation reaction of 1-aryl-2-iminoimidazolidines and arylisocyanates. 1-Aryl-2-iminoimidazolidines were synthesised in a two-step reaction from the respective anilines. The molecular structure of 1-(1-phenylimidazolidine-2-ylidene)-3-(4-chlorophenyl)urea (A2) has been determined by X-ray crystallography. The representatives of both investigated series were evaluated in behavioural animal tests. They exhibited significant, especially analgesic, activity on the animal central nervous system (CNS). They displayed substantial effect on the serotonine and catecholamine neurotransmission as well, at very low toxicity (LD(50) over 2000 mg kg(-1) i.p.). In the binding affinity tests they exhibited moderate affinity (on the micromolar level) toward opioid (mu) and serotonine (5HT(2)) receptors. The derivatives of series A had moderate affinity toward benzodiazepine (BZD) receptor as well. Distinctive differences observed in their activity spectra can be connected with the presence of particular structural features such as relative orientation of the two aromatic rings and the carbonyl moiety.     

Synthesis and anticancer evaluation of certain 4-anilinofuro[2,3-b]quinoline and 4-anilinofuro[3,2-c]quinoline derivatives

Certain linear 4-anilinofuro[2,3-b]quinoline and angular 4-anilinofuro[3,2-c]quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCI's 60 cancer cell lines. For the linear 4-anilinofuro[2,3-b]quinoline derivatives, 1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (5a) is the most cytotoxic with a mean GI50 value of 0.025 microM. Substitution at either furo[2,3-b]quinoline ring (2a, 2b, and 5b) or 4-anilino moiety (3-7) led to a decrease of cytotoxicity. For the angular 4-anilinofuro[3,2-c]quinoline derivatives, (E)-1-[3-(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone oxime (14a) exhibited potent inhibitory activities on UO-31, UACC-257, and UACC-62, with GI50 values of 0.03,<0.01, and<0.01 microM respectively. The same cytotoxicity profile was observed for its methyl counterpart, 14b, in which the GI50 values against UO-31, UACC-257, and UACC-62 was<0.01, 0.04 and<0.01 microM respectively. These results deserve full attention especially because 14a and 14b are relatively non-cytotoxic with the mean GI50 value of 7.73 and 8.91 microM respectively.     

Synthesis and 5-HT(1A), 5-HT(2A) receptor activity of new beta-tetralonohydantoins

A series of new 3-[4-(4-arylpiperazinyl)-butyl]-beta-tetralonohydantoins (8a-13a) were synthesized. The compounds exhibited high affinity for 5-HT(1A) receptors (K(i)=6 to 55 nM) combined with moderate-to-high 5-HT(2A) receptor affinities (K(i)=45 to 213 nM). The results of in vivo studies indicated that of the compounds tested, 3-[4-(4-phenylpiperazinyl)-butyl-beta-tetralonohydantoin (8a) showed features of full (pre- and postsynaptic) 5-HT(1A) receptor agonists, whereas compounds 9a-13a behaved like antagonists of postsynaptic 5-HT(1A) receptors; additionally, compound 13a produced an effect characteristic of presynaptic 5-HT(1A) receptor agonists. Moreover, compounds 8a and 10a-13a exhibited properties of 5-HT(2A) receptor antagonists. Due to the most interesting 5-HT(1A)/5-HT(2A) functional profile compounds 8a and 13a were further tested for their potential psychotropic activity. In fact, compound 8a (but not 13a) showed diazepam-like anxiolytic activity and behaved like a weak antidepressant.     

Synthesis of some new 4-styryltetrazolo[1,5-a]quinoxaline and 1-substituted-4-styryl[1,2,4]triazolo[4,3-a]quinoxaline derivatives as potent anticonvulsants

4-Methyltetrazolo[1,5-a]quinoxaline (3) was prepared by the azide cyclocondensation of 2-chloro-3-methylquinoxaline (2). The reaction of 3 with aromatic aldehydes furnished 4-styryltetrazolo[1,5-a]quinoxalines (4a-f). Compound 2, on treatment with hydrazine hydrate gave 2-hydrazino-3-methylquinoxaline (5). The ring closure of 5 was achieved by the reaction of orthoesters and trifluoroacetic acid to yield 4-methyl-1-(substituted)[1,2,4]triazolo[4,3-a]quinoxalines (7a-c). Further, reaction of 7a-c with different aromatic aldehydes furnished the title compounds, 4-styryl-1-(substituted)[1,2,4]triazolo[4,3-a]quinoxalines (8a-i) in good yield. In another scheme, the hydrazino compound 5 was treated with different aromatic aldehydes to yield corresponding N-arylidenehydrazino quinoxalines (6a-d). Further, the oxidative cyclization of hydrazones by nitrobenzene yielded 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines (7d-g), which on condensation with aromatic aldehydes gave the title compounds, 1-aryl-4-styryl[1,2,4]triazolo[4,3-a]quinoxalines (8j-u). The newly synthesized compounds have been characterized by FTIR, (1)H NMR, (13)C NMR and mass spectral data, followed by elemental analysis. Some of the compounds were screened for in vivo anticonvulsant activity. Few of them exhibited promising 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.     

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Part 3. Synthesis and pharmacological activity of 1-aryl-5,6(1H)dioxo-2,3-dihydroimidazo[1,2-a]imidazoles

Synthesis and pharmacological activity of 1-aryl-5,6(1H)dioxo-2,3-dihydroimidazo[1,2-a]imidazoles (D) are presented. The title compounds were obtained from 1-aryl-2-iminoimidazolidines (1) by cyclization reaction with oxalic acid derivatives-ethyl ester (2) or chloride (3). They were tested for pharmacological activity in animal and binding assay tests. With moderate acute toxicity (LD(50) approximately 200 mg kg(-1), i.p.), they exhibited significant analgesic and serotonergic activities as results of the 'writhing' and the 'hot plate' tests indicated, and reduced number of 'head twitch' episodes after 5-HTP (5-hydroxytryptophan) administration. Reversion of the antinociception produced in the 'writhing' test by small dose of naloxon (5 mg kg(-1)) can suggest an opioid-like mechanism of their analgesic activity. The probable receptor inhibition mechanism of their analgesic and serotonergic activity was confirmed in the binding assay tests (by radioligand displacement) toward the opioid mu and serotonin 5-HT(2) receptors. Additionally, they exhibited affinity toward the benzodiazepine (BZD) receptor as well, although in behavioral tests compounds did not produce any clear depressive effect on the central nervous system (CNS) of mice. Simple chemical structure of the title compounds, in comparison to other carbonyl derivatives of 1-aryl-2-iminoimidazolidine presented in this series of papers, underline very important role both of a hydrophobic moiety (aromatic ring) and polar groups (hydrogen-bond acceptors) in the serotonin receptor interaction. The co-existence of opioid-like, serotonergic and BZD receptor inhibition activity can be very interesting and can lead to creation of the novel group of antidepressants.     

New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants

A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to find a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. Title compounds were evaluated for in vitro activity on 5-HT1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities, and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (7) and 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (8) show values (nM) of K(i)=30 and 2.3 for 5-HT1A receptors and K(i)=30 and 12 for serotonin transporters, respectively. In GTPgammaS binding assays, compound 8 revealed antagonist properties to 5-HT1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism of action.     

Synthesis and antimicrobial activities of some new 1-(5-phenylamino-[1,3,4]thiadiazol-2-yl)methyl-5-oxo-[1,2,4]triazole and 1-(4-phenyl-5-thioxo-[1,2,4]triazol-3-yl)methyl-5-oxo- [1,2,4]triazole derivatives

Acetic acid ethyl esters containing 5-oxo-[1,2,4]triazole ring (2) were synthesized by the condensation of compounds 1a-f with ethyl bromoacetate in basic media. The reaction of compounds 2a-f with hydrazine hydrate led to the formation of acid hydrazides (3a-f). The treatment of compounds 3 with two divers aromatic aldehydes resulted in the formation of arylidene hydrazides as cis-trans conformers (4a,c,e,f, 5a,e,f). The thiosemicarbazide derivatives (6a,c,d,f) were afforded by the reaction of corresponding compounds 3 with phenylisothiocyanate. The treatment of compounds 6a,c,d,f with sulfuric acidic caused the conversion of side-chain of compounds 6a,c,d,f into 1,3,4-thiadiazol ring; thus, compounds 7a,c,d,f were obtained. On the other hand, the cyclization of compounds 6a,c,d,f in the presence of 2 N NaOH resulted in the formation of compounds 8a,c,d,f containing two [1,2,4]triazole rings which are linked to each other via a methylene bridge. Compounds 4a, f, 5a, 7a, d, f, 8a and d have shown antimicrobial activity against one or more microorganism, but no antifungal activity has been observed against yeast like fungi. Also inhibitory effect on mycelial growth by compounds 4e, 7d and 8f has been observed. Compounds 4c and 5f were found to possess antitumor active towards breast cancer.