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A number of 4-aminopyrazolo[3,4-b]pyridines 5-carboxylic acid esters (2−8) were synthesized and evaluated for their binding affinity at the A1, A2A, and A3 adenosine receptors (AR), in bovine cortical membranes, as well as for their affinity toward human A1AR (hA1AR). Some of the new compounds were characterized by a high affinity and selectivity toward the A1 receptor subtype, showing a significant improvement in comparison with other pyrazolo-pyridines previously reported in the literature. In particular the methyl ester 2h as well as the isopropyl ester 5h, both of them bearing a p-methoxyphenylethylamino side chain at the position 4, presented Ki values of 6 and 7 nM, respectively. To rationalize the relationships between structure and affinity of the novel compounds, a 3D QSAR model was also generated starting from compounds belonging to different classes of known A1AR antagonists.

In this paper we describe our structure-based ligand design, synthetic strategy, and structure−activity relationship (SAR) studies that led to the identification of thiocarbamates (TCs), a novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), isosteres of phenethylthiazolylthiourea (PETT) derivatives. Assuming as a lead compound O-[2-(phthalimido)ethyl]phenylthiocarbamate 12, one of the precursors of the previously described acylthiocarbamates (Ranise, A.; et al. J. Med. Chem. 2003, 46, 768−781), two targeted solution-phase TC libraries were prepared by parallel synthesis. The lead optimization strategy led to para-substituted TCs 31, 33, 34, 39, 40, 41, 44, 45, and 50, which were active against wild-type HIV-1 in MT-4-based assays at nanomolar concentrations (EC50 range:  0.04−0.01 μM). The most potent congener 50 (EC50 = 0.01 μM) bears a methyl group at position 4 of the phthalimide moiety and a nitro group at the para position of the N-phenyl ring. Most of the TCs showed good selectivity indices, since no cytotoxic effect was detected at concentrations as high as 100 μM. TCs 31, 37, 39, 40, and 44 significantly reduced the multiplication of the Y181C mutant, but they were inactive against K103R and K103N + Y181C mutants. Nevertheless, the fold increase in resistance of 41 was not greater than that of efavirenz against the K103R mutant in enzyme assays. The docking model predictions were consistent with in vitro biological assays of the anti-HIV-1 activity of the TCs and related compounds synthesized.

Novel 1,4,6-trisubstituted pyrazolo[3,4-d]pyrimidines are reported with preliminary in vitro activity data indicating that several of them are potent inhibitors (better than the reference compound) of Src phosphorylation of the breast cancer cells 8701-BC, known to overexpress Src. The ability of such compounds to significantly reduce 8701-BC cell proliferation suggests that this scaffold could be a promising lead for the development of antitumoral agents able to block Src phosphorylation of breast cancer cells.

We present a combined computational study aimed at identifying the three-dimensional structural properties required for different classes of compounds to show antagonistic activity toward the A1 adenosine receptor (AR). Particularly, an approach combining pharmacophore mapping, molecular alignment, and pseudoreceptor generation was applied to derive a hypothesis of the interaction pathway between a set of A1 AR antagonists taken from the literature and a model of the putative A1 receptor. The pharmacophore model consists of seven features and represents an improvement of the N⁶-C8 model, generally reported as the most probable pharmacophore model for A1 AR agonists and antagonists. It was used to build up a pseudoreceptor model able to rationalize the relationships between structural properties and biological data of, and external to, the training set. In fact, to further assess its statistical significance and predictive power, the pseudoreceptor was employed to predict the free energy of binding associated with compounds constituting a test set. While part of these molecules was also taken from the literature, the remaining compounds were designed and synthesized by our research group. All of the new compounds were tested for their affinity toward A1, A2a, and A3 AR, showing interesting antagonistic activity and A1 selectivity.

Starting with the heterocyclic α‐hydroxymethylene ketones (I), the title compounds (III) are prepared by reaction with 1,1'‐carbonyldiimidazole (II).

The Mannich bases (III) and (IV) are prepared by heating the indazolones (I), paraformaldehyde and the hydrochlorides (II) of secondary amines.

The aminomethylenequinazolinones (I) react with the sulfene (II), generated in situ from methanesulfonyl chloride and triethylamine, to give the adducts (III).

Cyclocondensation of the enaminones (III), derived from the enol (I) and the amines (II), with dichloro ketene gives the unstable furobenzopyranones (V) which are directly dehydrochlorinated and then aromatized to yield the title compounds (VII).

Phenyl chloro ketene (II) reacts with the aminomethylenecycloalkenones (I) to give the cycloadducts (III) which are dehydrochlorinated to yield the olefins (IV), together with (V).

The hydroxymethylene ketones (I) react with the amines (II) to give the aminomethylene derivatives (III).

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The 2‐dimethylaminomethylene‐3‐keto esters (III), prepared from the carboxylates (I) and dimethylformamide dimethyl acetal (II), react with methylhydrazine (IV) to form the pyrazolecarboxylates (V) and (VI).