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A new group of 5-(alkylamino)-9-isopropyl[1,2,4]triazolo[4,3- a ][1,8]naphthyridine derivatives bearing a CONHR group at the 6-position ( 1c – g ), designed to obtain new effective analgesic and/or anti-inflammatory agents, were synthesized and tested along with three new 9-alkyl-5-(4-alkyl-1-piperazinyl)- N,N -diethyl [1,2,4]triazolo[4,3- a ][1,8]naphthyridine-6-carboxamides ( 2b – d ). Besides, a new class of analogues of compounds 1 and 2 , bearing a Mannich base moiety at the 9-position ( 12a – d ), as well as the novel N,N -diethyl-5-(isobutylamino)-8-methyl-10-oxo-10 H -pyrimido[1,2- a ][1,8]naphthyridine-6-carboxamide ( 15 ) were prepared and tested. Compounds 1c – g exhibited very interesting anti-inflammatory properties in rats, whereas compounds 2b – d and 15 proved to be endowed with prevalent analgesic activity frequently associated with sedative effects in mice. On the contrary, the Mannich bases 12a – d resulted inactive. The most effective (80% inhibition of oedema) and potent (threshold dose 1.6 mg kg −1 with 31% inhibition of oedema) anti-inflammatory compound 1d did not show gastrolesive effects following 100 mg kg −1 oral administration in rats. [ABSTRACT FROM AUTHOR]

Abstract: The multistep preparation of the new 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones 6a–o, and of the two isomers 10-ethyl-2-(diethylamino)pyrimido[1,2-a]benzimidazol-4(10H)-one 6p and 10-ethyl-4-(diethylamino)pyrimido[1,2-a]benzimidazol-2(10H)-one 13, as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca2+ ionophore A23187 were here described. Nine out of fifteen 2-(1-piperazinyl)derivatives (6g–o) showed good inhibitory properties towards all the platelet aggregation agonists used. Moreover, a molecular modelling study has been performed on two of the best compounds of this series (6i and 6o) to confirm in silico their interactions with the catalytic site of human platelet PDE3, using the X-ray data of the PDE3B isoform in complex with an inhibitor. [Copyright &y& Elsevier]

Abstract: The [1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamide derivatives 5-amino (2) or 5-alkoxy (3) substituted and the 5-amino[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide derivatives (4), designed to obtain new effective analgesic and/or anti-inflammatory agents were synthesized. Ten compounds 2 and 4 showed an interesting analgesic activity: the most potent ones are 2j (36% inhibition, P <0.05) and 4b (77% inhibition, P <0.01) at 6.25 and 25mgkg−1 doses, respectively. Compounds 2i–l and 4c showed notable anti-inflammatory properties: the most potent ones are 2i (68% inhibition, P <0.01) and 2l (42% inhibition, P <0.05) at 12.5 and 6.25mgkg−1 doses, respectively. The replacement in compounds 2 of the N-substituted 5-amino substituents with similar alkoxy groups usually afforded less active compounds 3. [Copyright &y& Elsevier]

Abstract: On the basis of the good anti-inflammatory properties shown by the 9-alkyl-N,N-dialkyl-5-(alkylamino)[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 1, a series of analogues of such compounds, in which the 9-alkyl substituent was replaced by an ester or amide group (compounds 3a–i), was prepared and tested (inhibition of carrageenan-induced paw edema in the rat). Also two 5-(N-alkyl,N-acylamino) derivatives (compounds 4a,b) were synthesized and evaluated for the same purpose. Even though the general trend for these new [1,2,4]triazolo[4,3-a][1,8]naphthyridine derivatives was a decrease in activity compared with compounds 1, some of the new synthesized compounds exhibited still good anti-inflammatory properties. [Copyright &y& Elsevier]

Abstract: A series of 11 new 9H-bis-[1,2,4]triazolo[4,3-a:3′,4′-d] [1,5]benzodiazepine derivatives 8e–o was synthesized. Ten of these compounds (8e–m,o), along with four analogues (8a–d) (previously synthesized by us) were tested in vitro in order to evaluate their cytotoxic and anti-HIV-1 properties. In this connection other six original compounds, i.e., five 9-substituted compounds prepared starting from the 6,12-diphenylderivative 8c (compounds 10, 11, 12, 13a,b) and the bis-triazolone derivative 14, were synthesized and tested for the same purpose. While none of the 20 compounds tested exhibited any appreciable anti-HIV-1 activity, some of them exhibited interesting cytotoxic properties, the best results being shown by compounds 8c,d,k and 11 (CC50 range=3–12 μM). Therefore, these four compounds were further evaluated for their antiproliferative activity against a panel of human tumor cell lines; actually, compounds 8d, 8k and 11 showed antiproliferative properties against either or both leukemia- and lymphoma-derived cell lines in the low micromolar range. [Copyright &y& Elsevier]

Abstract: Most N,N-disubstituted 5-amino-N,N-diethyl-9-isopropyl [1,2,4]triazolo[4,3-a] [1,8]naphthyridine-6-carboxamides 9 (compounds 9a, c–i) and the N-monosubstituted one 8c were obtained by treating with excess amine the corresponding 5-chloroderivative 7a, which was in turn prepared by cyclocondensation of the 2,4-dichloro-N,N-diethyl-1,8-naphthyridine-3-carboxamide (4a) with isobutyrohydrazide. Compounds 8a,b and 9b,j–m were obtained according with the methods shown in Scheme 1. The above now synthesized compounds, along with the previously described 8d and 8e, were tested for their anti-inflammatory, analgesic and antipyretic properties, and most compounds also for their effect on spontaneous mice locomotor activity and their acute gastrolesivity in rats. Several compounds showed potent anti-inflammatory and/or analgesic activities, and all the compounds tested proved to be completely lacking in acute gastrolesivity. In many cases compounds 8 and 9 produced hypothermic effect, usually at high doses. On the whole, the N-monosubstituted 5-aminoderivatives 8 appeared to be more potent anti-inflammatory agents than the corresponding N,N-disubstituted 9, whereas these latter compounds exhibited higher analgesic activity. [Copyright &y& Elsevier]

Pursuing our chemical and biological studies in this field, we described the multistep preparation of the new 5-, 6-, or 7-alkoxy and 7-alkoxy-8-methyl substituted 4-(1-piperazinyl)coumarins 5d-v, as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca2+ ionophore A23187. Compounds 5h-j,p,r-u showed notably high activity towards all the platelet aggregation inducers used, and the most active one, 8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin (5t), proved to be a potent in vitro antiplatelet agent. [Copyright &y& Elsevier]

The N-substituted tricyclic 2-aminochromone derivatives 1a, 2a, and 2b were obtained by treating the corresponding (methylthio) or (methylsulfinyl) derivatives 10, 11, or 12, respectively, with an excess of the proper amines. Compound 2c was synthesized through the reaction of 2-naphthol with the ethyl N,N-diphenylmalonamate/POCl3 reagent 14. The N-substituted 4-aminocoumarin bicyclic and tricyclic derivatives 5–8 were prepared by treating the corresponding chloro derivatives with the excess suitable amines. Compounds 1, 2, 5–8 were tested in vitro for their antiproliferative activity (DNA synthesis inhibition in Ehrlich cells) and cytotoxicity (MTT test in HeLa cells). The inhibitory properties of three selected compounds (5c, 5e, 7c) on protein and RNA syntheses in Ehrlich cells were also evaluated. Among the 27 compounds tested, 10 4-aminocoumarin derivatives 5–8 and two 2-aminochromone derivatives (1a and 2a) showed an appreciable antiproliferative activity (IC50 range: 1.74–13.8 μM), whereas only four compounds 5–8 exhibited a comparable cytotoxic activity (IC50 range: 4.95–12.9 μM). [Copyright &y& Elsevier]

The reaction of proper N,N-dialkyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines (1) with N-chlorosuccinimide afforded their 4-chloroderivatives 3 which in turn were treated with cyclic amines to give the corresponding 4,5-diaminoderivatives 4. The N,N-dialkyl-4H-imidazo[1,2-a][1,5]benzodiazepin-5-amines (5) were prepared starting from suitable 4-(dialkylamino)-1,3-dihydro-2H-1,5-benzodiazepin-2-ones (8), through multistep synthetic routes. At the 200 mg kg−1 os dose, some compounds 3 and 4 showed notable analgesic or anti-inflammatory activity but no antipyretic properties, whereas the 5-(dibutylamino) derivatives 5b and 5f proved to be significantly endowed with all these activities. Almost all the compounds 3, 4 and 5 did not show acute toxicity in mice up to 800 mg kg−1 os dose. [Copyright &y& Elsevier]

Abstract: On the basis of the very interesting pharmacological properties shown by the 5-amino[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamide derivatives 1, previously described by us, we have now prepared the 5-aminoimidazo[1,2-a][1,8]naphthyridine-6-carboxamide derivatives 2a–o (a new structural class) whose tricyclic system is isosteric to that of compounds 1. Both compounds 2 and some new properly substituted compounds 1 (1f–k) now synthesized were tested in vivo for their analgesic and anti-inflammatory activities: on the whole, compounds 2 showed notable analgesic properties, whereas many compounds 1 exhibited a very potent anti-inflammatory activity, coupled to scarce analgesic activity. All the effective compounds proved to be completely devoid of acute gastrolesivity (gastric damage) in rats (at the 200mgkg−1 oral dose). [Copyright &y& Elsevier]

Abstract The limited treatment options against influenza virus along with the growing public health concerns regarding the continuous emergence of drug-resistant viruses make essential the development of new anti-flu agents with novel mechanisms of action. One of the most attractive targets is the interaction between two subunits of the RNA-dependent RNA polymerase, PA and PB1. Herein we report the rational design of hybrid compounds starting from a 3-cyano-4,6-diphenylpyridine scaffold recently identified as disruptor of PA-PB1 interactions. Guided by the previously reported SAR data, a library of amino acid derivatives was synthesized. The biological evaluation led to the identification of new PA-PB1 inhibitors, that do not show appreciable toxicity. Molecular modeling shed further lights on the inhibition mechanism of these compounds. Graphical abstract Image 1 Highlights • Hybrid compounds composed by the active cyano-pyridine core and the PB1 N last amino acid sequence were designed. • A library of cyano-pyridine compounds was synthesized and tested as inhibitor of PA-PB1 interaction. • Minireplicon assays for some compounds of the series confirmed the on-target activity. • Compound 7c was identified as a new hit compound endowed with a good anti-influenza activity and no cytotoxicity emerged. [ABSTRACT FROM AUTHOR]

In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3- d ]pyrimidines, compounds 8a-j , and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AblT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3- d ]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC 50 value of 7.1 μM. [ABSTRACT FROM AUTHOR]

Abstract: The effects on the inhibition potencies of monoamine oxidase isoforms A (MAO-A) and B (MAO-B) depending upon changes in the physicochemical properties (size, shape, H-bonding, lipophilicity, etc.) of substituents at the C4 position of 2H-chromen-2-one derivatives were extensively investigated, and the results significantly added to our knowledge on this class of MAO inhibitors. All the 67 examined compounds showed high MAO-B selectivity, some of them achieving potency in the low nanomolar range. In particular, the 7-metachlorobenzyloxy-4-oxyacetamido-2H-chromen-2-one (entry 62) showed single digit nanomolar MAO-B potency (IC50 = 3.1 nM) and high selectivity over the MAO-A isoform (selectivity ratio = 7244). The great variety of the investigated substituents at C4 of the 2H-chromen-2-one nucleus, combined with binding models generated from docking studies carried out on selected compounds, allowed us to shed light on the main molecular requirements for potent and selective MAO-B inhibition, highlighting the dominant role of the steric effects. Interestingly, many of the designed substituents could be metabolically related to each other (e.g., CH3/CH2OH/CHO/COOH; NH2/NHCH3, NHAc), and therefore the results obtained may help in predicting the in vivo activity of some putative metabolites of lead MAO-B inhibitors. [Copyright &y& Elsevier]

As a further part of our chemical and biological studies in this field, we describe the multistep preparations of the properly substituted 2-(1-piperazinyl)chromone 1b, 4-(1-piperazinyl)coumarins 5c–h, their linear benzo-fused analogues 4a,b and 8a,b, bicyclic (15e–g) and tricyclic (15h,i) fused derivatives of 6-(1-piperazinyl)pyrimidin-4(3H)-one, and of the 4H-pyrido[1,2-a]pyrimidine derivatives 9b,c. The in vitro evaluation of their inhibitory properties towards human platelet aggregation induced in platelet-rich plasma by ADP, collagen, or the Ca 2+ionophore A23187 showed the high activity of compounds 5d–g and 15f,g,i, among which the coumarins 5g and 5d proved to be, in that order, the most effective in vitro antiplatelet agents until now synthesized by us. Thus, in order to consider also the 4-aminocoumarin structural class, we developed a new statistically significant 3-D QSAR model, more general than the one previously obtained, through a further CoMFA study based on the antiplatelet activity data and molecular steric and electrostatic potentials of both the previously studied and herein described compounds. [Copyright &y& Elsevier]

[Display omitted] • Nanocomposites based on HNTs/pyrazolo[3,4- d ]pyrimidine derivatives were developed. • Kinetic release was performed in physiological pH conditions. • Their antitumoral activity was evaluated on three cancer cell lines. • Cell cycle was investigated, showing cells arrested in the G1 phase. • Molecular dynamics studies showed an interaction with the active site of CDK2. Uncontrolled cell proliferation is a hallmark of cancer as a result of rapid and deregulated progression through the cell cycle. The inhibition of cyclin-dependent kinases (CDKs) activities is a promising therapeutic strategy to block cell cycle of tumor cells. In this work we reported a new example of nanocomposites based on halloysite nanotubes (HNTs)/pyrazolo[3,4- d ]pyrimidine derivatives (Si306 and Si113) as anticancer agents and CDK inhibitors. HNTs/Si306 and HNTs/Si113 nanocomposites were synthesized and characterized. The release kinetics were also investigated. Antitumoral activity was evaluated on three cancer cell lines (HeLa, MDA-MB-231 and HCT116) and the effects on cell cycle arrest in HCT116 cells were evaluated. Finally, molecular dynamics simulations were performed of the complexes between Si113 or Si306 and the active site of both CDK 1 and 2. [ABSTRACT FROM AUTHOR]