Design,synthesis and molecular docking of pyrazolo [3,4d] thiazole hybrids as potential anti-HIV-1 NNRT inhibitors

A series of pyrazolo[3.4,d]thiazole hybrids 6 were synthesized from 5-arylidene-2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones 5. The 5-arylidene-2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones 5 were synthesized from 2-amino-4-arylthiazoles 1 and 2-chloro-acetamido-4-arylthiazoles 2 via the formation of 2-imino-3-(4-substituted-arylthiazol-2-yl)-thiazolidin-4-ones 3 using substituted aldehydes 4. The 5-acrylidene derivative 5 on cyclisation with phenyl hydrazine give the pyrazolo [3, 4, d] thiazole derivatives 6. The obtained pyrazolo [3.4, d]thiazole derivatives were studied as anti-HIV-1 NNRT inhibitors. It was found that these compounds might have potent RT inhibition activity.     

Design, synthesis, and discovery of 3-piperazinyl-3,4-dihydro-2(1H)-quinolinone derivatives: a novel series of mixed dopamine D2/D4 receptor antagonists

3-Piperazinyl-3,4-dihydro-2(1H)-quinolinone derivatives (delta-lactams) were designed, synthesized, and identified as a new series of mixed dopamine D2/D4 receptor antagonists. To further the structure-activity relationship (SAR) study, 3-piperazinylindolin-2-ones (gamma-lactams) and 3-piperazinyl-3H,4H,5H-benzo[f]azepin-2-ones (epsilon-lactams) were also prepared and examined.     

Urea/thiourea catalyzed, solvent-free synthesis of 5-arylidenethiazolidine-2,4-diones and 5-arylidene-2-thioxothiazolidin-4-ones

An efficient and organo-catalyzed method has been developed for the synthesis of 5-arylidenethiazolidine-2,4-diones and 5-arylidene-2-thioxothiazolidin-4-ones via Knoevenagel condensation of arylaldehydes 1 and 2,4-thiazolidinedione 2a/2-thioxothiazolidin-4-one 2b under mild conditions. Urea-adduct 4 and azomethine 5 also afford arylidene-products 3 by reacting with 2a-b via addition-elimination reaction. This protocol has the features of use of inexpensive, ecofriendly readily available, effective catalyst system viz. urea/thiourea, avoidance of volatile solvents, excellent yield and simple work-up procedure.     

An efficient route to novel 4,5-di- and 2,4,5-tri substituted imidazoles from imidazo[1,5-a]-1,3,5-triazine (5,8-diaza-7,9-dideazapurine) derivatives

Two new types of imidazole derivatives: N-(2-R1-5-R2-1H-imidazol-4-yl) thioureas 7a-g and N-(2-R1-5-R2-1H-imidazol-4-yl) formamides 8b,c,g were obtained in high yields by the hydrolytic degradation of 6-R1-8-R2-2-thioxo-2,3-dihydroimidazo[1,5-a]-1,3,5-triazin-4(1H)-ones 5a-g and 6-R1-8-R2-imidazo[1,5-a]-1,3,5-triazin-4(3H)-ones 6b,c,d, respectively. The tautomeric preferences of the new imidazoles were determined.     

6-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors

Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.     

Synthesis and structure-activity relationships of pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones as corticotropin-releasing factor-1 receptor antagonists

Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.     

Synthesis and SAR of 5-, 6-, 7- and 8-aza analogues of 3-aryl-4-hydroxyquinolin-2(1H)-one as NMDA/glycine site antagonists

A series of 5-, 6-, 7- and 8-aza analogues of 3-aryl-4-hydroxyquinolin-2(1H)-one was synthesized and assayed as NMDA/glycine receptor antagonists. The in vitro potency of these antagonists was determined by displacement of the glycine site radioligand [(3)H]5,7-dicholorokynurenic acid ([(3)H]DCKA) in rat brain cortical membranes. Selected compounds were also tested for functional antagonism using electrophysiological assays in Xenopus oocytes expressing cloned NMDA receptor (NR) 1A/2C subunits. Among the 5-, 6-, 7-, and 8-aza-3-aryl-4-hydroxyquinoline-2(1H)-ones investigated, 5-aza-7-chloro-4-hydroxy-3-(3-phenoxyphenyl)quinolin-2-(1H)-one (13i) is the most potent antagonist, having an IC(50) value of 110 nM in [(3)H]DCKA binding and a K(b) of 11 nM in the electrophysiology assay. Compound 13i is also an active anticonvulsant when administered systemically in the mouse maximum electroshock-induced seizure test (ED(50)=2.3mg/kg, IP).     

Design and evaluation of non-carboxylate 5-arylidene-2-thioxo-4-imidazolidinones as novel non-competitive inhibitors of protein tyrosine phosphatase 1B

Protein tyrosine phosphatase 1B (PTP1B) acts as a negative regulator of insulin and leptin signalling and is crucially involved in the development of type 2 diabetes mellitus, obesity, cancer and neurodegenerative diseases. Pursuing our efforts to identify PTP1B inhibitors endowed with drug-like properties, we designed and evaluated 3-aryl-5-arylidene-2-thioxo-4-imidazolidinones (7) as a novel class of non-carboxylate PTP1B inhibitors. In agreement with our design, kinetic studies demonstrated that selected compounds 7 act as reversible, non-competitive inhibitors of the target enzyme at low micromolar concentrations. Accordingly, molecular docking experiments suggested that these inhibitors can fit an allosteric site of PTP1B that we previously individuated. Moreover, cellular assays demonstrated that compound 7e acts as a potent insulin-sensitizing agent in human liver HepG2 cells. Taken together, our results showed that these non-competitive PTP1B inhibitors can be considered promising lead compounds aimed to enhance druggability of the target enzyme and identify novel antidiabetic drugs.     

Synthesis,antimicrobial, and mosquito larvicidal activity of 1-aryl-4-methyl-3,6-bis-(5-methylisoxazol-3-yl)-2-thioxo-2,3,6,10b-tetrahydro-1H-pyrimido[5,4-c]quinolin-5-ones

A series of 1-aryl-4-methyl-3,6-bis-(5-methylisoxazol-3-yl)-2-thioxo-2,3,6,10b-tetrahydro-1H-pyrimido[5,4-c]quinolin-5-ones (6a–h) have been synthesized by cyclization of ethyl-3-aryl-4-(2-chlorophenyl)-6-methyl-1-(5-methylisoxazol-3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates 4a–h with 3-amino-5-methylisoxazole 5. Compounds 4a–h were obtained by Biginelli reaction, by condensation of aromatic aldehyde 1, ethyl acetoacetate 2, and isoxazolyl thioureas 3 in a one-pot reaction catalyzed by ceric ammonium nitrite (CAN). Compounds 6a–h were tested for their antibacterial and antifungal activities against various bacterial and fungal strains. The results showed that these compounds exhibited good antibacterial and antifungal activity compared with that of standard antibiotics. Mosquito larvicidal activity of the newly synthesized compounds 6a–h is also studied against fourth instar larvae Culex quinquefasciatus. Some of the compounds are proved to be lethal for mosquito larvae.     

Identification and characterization of amino-piperidinequinolones and quinazolinones as MCHr1 antagonists

Several potent, functionally active MCHr1 antagonists derived from quinolin-2(1H)-ones and quinazoline-2(1H)-ones have been synthesized and evaluated. Pyridylmethyl substitution at the quinolone 1-position results in derivatives with low-nM binding potency and good selectivity with respect to hERG binding.     

2-Substituted 4-, 5-, and 6-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]pyridazin-3(2H)-ones and 2-substituted 4,5-bis[(1E)-3-oxo-3-phenylprop-1-en-1-yl]pyridazin-3(2H)-ones as potent platelet aggregation inhibitors: design, synthesis, and SAR studies

A set of regioisomeric 2-substituted pyridazin-3(2H)-ones containing a 3-oxo-3-phenylprop-1-en-1-yl fragment at either position 4, 5 or 6 and 2-substituted pyridazin-3(2H)-ones containing the same fragment both at positions 4 and 5 have been synthesized and evaluated as antiplatelet agents. The study allows the identification of a new highly potent platelet aggregation inhibitor (4c).     

3,4-Dihydronaphthalen-1(2H)-ones: novel ligands for the benzodiazepine site of alpha5-containing GABAA receptors

A series of substituted 3,4-dihydronaphthalen-1(2H)-ones with high binding affinity for the benzodiazepine site of GABAA receptors containing the alpha5-subunit has been identified. These compounds have consistently higher binding affinity for the GABAA alpha5 receptor subtype over the other benzodiazepine-sensitive GABAA receptor subtypes (alpha1, alpha2 and alpha3). Compounds with a range of efficacies for the benzodiazepine site of alpha5-containing GABAA receptors were identified, including the alpha5 inverse agonist 3,3-dimethyl-8-methylthio-5-(pyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one 22 and the alpha5 agonist 8-ethylthio-3-methyl-5-(1-oxidopyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one 19.     

Synthesis and SAR of 3- and 4-substituted quinolin-2-ones: discovery of mixed 5-HT(1B)/5-HT(2A) receptor antagonists

Quinolin-2-ones bearing a heteroaryl-piperazine linked by a two carbon chain at the 3- or 4-position were synthesised and evaluated as mixed 5-HT(1B)/5-HT(2A) receptor antagonists. Potent mixed antagonists were obtained with thieno[3,2-c]pyridine derivatives. In this series, compound 2.1 (SL 65.0472) proved to be functional antagonist at both the 5-HT(2A) receptor (rat in vivo 5-HT-induced hypertension model) and the 5-HT(1B) receptor (dog in vitro saphenous vein assay).     

Tricyclic 3,4-dihydropyrimidine-2-thione derivatives as potent TRPA1 antagonists

The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers.     

Exploration of antimicrobial and antioxidant potential of newly synthesized 2,3-disubstituted quinazoline-4(3H)-ones

A series of 2-(chloromethyl)-3-(4-methyl-6-oxo-5-[(E)-phenyldiazenyl]-2-thioxo-5,6-dihydropyrimidine-1(2H)-yl)quinazoline-4(3H)-ones 9a-j was synthesized by treating 2-(chloroacetyl)amino benzoic acid with 3-amino-6-methyl-5-[(E)-phenyldiazenyl]-2-thioxo-2,5-dihydropyrimidine-4(3H)-one 8a-j and was screened for in vitro antibacterial activities against a representative panel of Gram-positive and Gram-negative bacteria. The compounds were synthesized in excellent yields and the structures were corroborated on the basis of IR, ¹H NMR, Mass and elemental analysis data. All the synthesized compounds elicited the potent inhibitory action against all the tested bacterial stains. Furthermore, in order to explore the antioxidant potential of newly synthesized compounds, the free radical scavenging activity measurement were performed by the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay method. It is revealed from the antioxidant screening results that the compounds 9c and f manifested profound antioxidant potential.     

Selective synthesis and reactions of 6-substituted-2-beta-galactosyl-1,2,4-triazines of potential anticancer activity

Selective synthesis and reactions of different 6-substituted-2-beta-D-galactosyl-3-thioxo-2,3-dihydro-1,2,4-triazin-5(4H)-ones using the developed amino or aryl protecting group strategy were investigated. Primary human anticancer screening of twelve selected compounds (in vitro) resulted in an active compound against both MCF7 (Breast) and SF-268(CNS) cell lines.     

Synthesis and pharmacological investigation of novel 1-substituted-4-phenyl-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones as a new class of H1-antihistaminic agents

A series of novel 1-substituted-4-phenyl-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones 7 were synthesized by the cyclization of 2-hydrazino-3-phenylquinazolin-4(3H)-one 6 with various one carbon donors. The starting material 2-hydrazino-3-phenylquinazolin-4(3H)-one 6, was synthesized from aniline 1 by a novel innovative route. When tested for their in vivo H(1)-antihistaminic activity on conscious guinea pigs all the test compounds protected the animals from histamine induced bronchospasm significantly, whereas the compound 1-methyl-4-phenyl-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-one 7b (percentage protection 70.7%) was found to be equipotent with the reference standard chlorpheniramine maleate (percentage protection 71%). These compounds show negligible sedation ( approximately 5%) when compared to the reference standard (26%). Hence they could serve as prototype molecules for future development.     

5-Arylamino-1,2,4-triazin-6(1H)-one CRF1 receptor antagonists

A series of 5-arylamino-1,2,4-triazin-6(1H)-ones was synthesized and evaluated as antagonists at the corticotropin releasing factor receptor. Formation of CYP-mediated oxidative reactive metabolites previously observed in a related N³-phenylpyrazinone structure was minimized by incorporation of the additional ring nitrogen found in the triazinones.     

Synthesis and evaluation of 4- and 5-pyridazin-3-one phenoxypropylamine analogues as histamine-3 receptor antagonists

A novel series of 4-pyridazin-3-one and 5-pyridazin-3-one analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship revealed the 5-pyridazin-3-ones 8a and S-methyl 8b had excellent human and rat H(3)R affinities, and acceptable pharmacokinetic properties. In vivo evaluation of 8a showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG/EMG model.     

1,5-Dihydro-benzo[e][1,4]oxazepin-2(1H)-ones containing a 7-(5'-cyanopyrrol-2-yl) group as nonsteroidal progesterone receptor modulators

A series of novel 7-(5'-cyanopyrrol-2-yl) substituted benzo[1,4]oxazepin-2-ones were prepared and tested for their progesterone receptor (PR) agonist or antagonist activity in the alkaline phosphatase assay using the human T47D breast carcinoma cell line. Both PR agonists and antagonists were achieved with an appropriate choice of 5-substitution. Several analogs were potent PR agonists (e.g., 12 and 13) or PR antagonists (e.g., 18) with good selectivity over other steroid receptors.