Donatella Boschi

Mechanisms of Liposomes/Water Partitioning of (p-Methylbenzyl)alkylamines

AbstractPurpose. The objective of this study was to compare and interpret the variations in lipophilicity of homologous (p-methylbenzyl)alkylamines (MBAAs) in isotropic (octanol/water) and anisotropic (zwitterionic liposomes/water) system. Methods. Two experimental approaches were used, namely the pH-metric method to measure lipophilicity parameters in octanol/water and liposomes/water systems, and changes in NMR relaxation rates to validate the former method and to gain additional insights into the mechanisms of liposomes/water partitioning. Results. For long-chain homologues (N-butyl to N-heptyl), the octanol/ water and liposomes/water systems mostly expressed hydrophobicity. In contrast, the lipophilicity of the shorter homologues (N-methyl to N-propyl) in the two systems expressed various electrostatic and polar interactions. Conclusions. The study sheds light on the molecular interactions between zwitterionic liposomes and amphiphilic solutes in neutral and cationic form.

Nitrooxymethyl-Substituted Analogues of Rofecoxib: Synthesis and Pharmacological Characterization

Nitrooxymethyl‐substituted derivatives of Rofecoxib were synthesized and tested for their cyclooxygenase (COX)‐inhibiting activity in whole human blood, vasodilator potency on rat aorta strips, and for their capacity of inhibiting platelet aggregation of human platelet‐rich plasma. The results show that their potency and selectivity in inhibiting COX isoforms, as well as their anti‐aggregatory properties, are closely dependent on the position at which the NO‐donor nitrooxymethyl function is introduced into the Rofecoxib scaffold. All the products were capable of dilating rat aorta strips precontracted with phenylephrine in a dose‐dependent manner, through a cGMP‐dependent mechanism. Compound 10 emerged as a quite potent COX‐2‐selective inhibitor endowed with good vasodilator activity. Interestingly, compound 19 behaved as a potent selective COX‐1 inhibitor, and displayed good vasodilator and anti‐aggregatory properties. The hydroxymethyl derivatives, potential metabolites of the nitrooxymethyl analogues, were similarly studied for a comparison.

Multitarget drugs: Focus on the NO-donor hybrid drugs

The article addresses the design of multitarget drugs, namely, compounds capable of interacting with more than one target simultaneously. These agents could be useful tools in the therapy of complex diseases such as cardiovascular and inflammatory diseases. An interesting case of multitarget compounds are nitric oxide (NO)-donor hybrids, structures which combine the physiological properties of NO with those of a lead drug. In particular, the authors discuss the symbiotic approach used to design NO-donor nonsteroidal anti-inflammatory drugs (NO-NSAIDs) and NO-donor antioxidants. The former could be useful agents in the treatment of anti-inflammatory diseases being devoid of gastro- and cardiotoxicity, the latter could be a valid approach to the treatment of many cardiovascular diseases.

Novel nitro-oxy derivatives of celecoxib for the regulation of colon cancer cell growth.

Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) developed as a selective inhibitor of cyclooxygenase-2 (COX-2). Despite the associated cardiovascular toxicity risk, celecoxib has been found to be effective in reducing cancer risk in animal and human studies. In the present study the antiproliferative activity of novel nitro-oxy-methyl substituted analogues of celecoxib (NO-cel), potentially less cardiotoxic, has been investigated in vitro on human colon cancer cells and compared with action of the parent drug. Moreover, experiments were performed in order to evaluate whether COX-2 pharmacological inhibition may affect beta-catenin/E-cadherin signalling pathway. All the tested analogues of celecoxib exerted a significant antiproliferative activity on COX-2 positive HT-29 human colon cancer cells, being less effective on the COX-2 negative SW-480 human colon cancer cell line. In particular, the analogue displaying two nitro-oxy functions fully mimicked the known inhibitory properties of celecoxib, including inhibition of COX-2, as well as of ERK/MAPK and beta-catenin signalling pathways. Interestingly, the latter compound also elicited a strong reorganization of the beta-catenin/E-cadherin complex, which has been suggested to be relevant for colon carcinogenesis. On these premises, NO-cel analogues of celecoxib can represent promising colon cancer chemopreventive agents potentially able to affect colon cancer development.

Furazan and furoxan sulfonamides are strong α-carbonic anhydrase inhibitors and potential antiglaucoma agents

A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3-5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3-5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39-42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma.

Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches

Bioisosterism and scaffold hopping are two widely used approaches in medicinal chemistry for the purpose of lead optimization. The study highlights the physicochemical properties of the 4-hydroxy-1,2,3-triazole scaffold, a less investigated heterocyclic system. Synthetic strategies to obtain different N-substituted 4-hydroxy-1,2,3-triazole isomers are presented, and their role as possible isosteres of the carboxylic acid is discussed. The aim is to use this system to modulate the acidic moieties present in lead compounds and, at the same time, to regiodirect substituents in set directions, through targeted substitution on the three nitrogenatoms of the triazole ring. Through this approach, compounds having enhanced binding affinity, will be sought. Two examples of bioisosteric applications of this moiety are presented. In the first example, a classical bioisosteric approach mimicking the distal (S)-glutamic acid carboxyl group using the 4-hydroxy-1,2,3-triazole moiety is applied, to obtain two promising glutamate analogs. In the second example, a scaffold hopping approach is applied, replacing the phenolic moiety present in MDG-1-33A, a potent inhibitor of Onchocerca volvulus chitinase, with the 4-hydroxy-1,2,3-triazole scaffold. The 4-hydroxy-1,2,3-triazole system appears to be useful and versatile in drug design.

Synthesis and in vitro antimicrobial activities of new (cyano-NNO-azoxy)pyrazole derivatives

The antibacterial and antifungal activity of a series of products, in which the 1,5-dimethyl-4-(cyano-NNO-azoxy)pyrazol-3-yl and 1,3-dimethyl-4-(cyano-NNO-azoxy)pyrazol-5-yl moieties were linked to pyridine, pyrazole, isoxazole, thiophene and the furan ring, were examined. No molecule displayed activity against the gram-negative bacteria tested. Conversely, some compounds displayed activity against two Staphylococcus aureus strains, including the methicillin resistant strain. All compounds displayed interesting antifungal activity, the most active compound of the series being the thiophene derivative 7a. This compounds activity against Candida krusei and Candida glabrata (MIC=0.25 and 0.5 μg/mL, respectively), two fungal species resistant to azoles, is noteworthy. The presence of the cyano function appeared essential for activity.

Studies on agents with mixed NO-dependent and calcium channel antagonistic vasodilating activities.

AbstractPurpose. To obtain new cardiovascular agents with mixed Ca2+-channel antagonistic and NO-donor properties, a series of “hybrid” 1,4-dihydropyridines (1,4-DHPs), bearing NO-donating furoxan moieties on the 3-positioned lateral ester chain were synthesized and pharmacologically characterized. Furazan analogues were also prepared and investigated for control purposes, because they are unable to release NO.4Methods. Synthesis of the models was achieved by a modified Hantzsch approach. All of the final furoxan 1,4-DHPs were assessed for their ability to produce nitrite in the presence of a large excess of cysteine by the Griess reaction. Vasodilating activity was evaluated on rat aorta and expressed as EC50 and EC50MB values, obtained in the absence and in the presence of methylene blue (MB) respectively, a well-known guanylate cyclase inhibitor. Affinities to 1,4-DHP receptor on Ca2+-channels, expressed as IC50 values, were determined through displacement experiments of [3H]-nitrendipine on rat cortex homogenates. Results. Some hybrid compounds (derivatives 15a, 15b, 16a, and 16b) displayed vasodilating activity depending predominantly on their Ca2+-channel blocker properties. By contrast, some others (derivatives 17a, 17b, and 21) behaved as well-balanced hybrids with mixed Ca2+-channel blocking and NO-dependent vasodilating activities. Conclusion. This work demonstrates the possibility of obtaining well-balanced hybrids endowed with mixed NO-donor and Ca2+-channel blocker properties using appropriate 1,4-DHP and furoxan moieties. A procedure for the individual evaluation of the NO-dependent vasodilator component and that due to Ca2+-channel blocking is proposed.

Searching for balanced hybrid NO-donor 1,4-dihydropyridines with basic properties.

AbstractPurpose. Model compounds containing NO-donor furoxan moieties at the 3-positioned basic lateral chain of 1, a 1,4-dihydropyridine related to nicardipine, were synthesized in order to study their vasodilating activity as well as their basic and lipophilic behaviour. Methods. All the compounds were obtained by a modified Hantzsch approach. Potentiometry was used to determine pKa and lipophilicity descriptors. The furoxan 4-aryl-1,4-dihydropyridines were assessed for their ability to release nitrite, in the presence of a large excess of cysteine, by the Griess reaction. Vasodilating activity of the products in the absence and in the presence of ODQ, a well-known guanylate cyclase inhibitor, was evaluated on rat thoracic aorta. Results. The compounds display low basicity values and for this reason their log Ds at physiological pH are identical to the log Ps of the neutral forms. Products 2, 3 display vasodilating action principally dependent on their Ca2+-antagonist properties, whereas 4 behaves as a well-balanced hybrid with mixed Ca2+-channel blocker and NO-dependent vasodilator activities. Conclusions. Nitrogen containing lateral chain at the 3-position of 1 is a suitable molecular region to be modified in order to obtain well-balanced furoxan NO-donor 1,4-DHPs. This manipulation produces a decrease in the basicity. General analysis of pKa and lipophilicity descriptors of these new DHPs suggest that molecular flexibility could influence both their basicity and log PI.

Structural investigation of Ca2+ antagonists benzofurazanyl and benzofuroxanyl-1,4-dihydropyridines

Abstract The structure of Ca 2+ channel blockers benzofurazanyl- and benzofuroxanyl-1,4-dihydropyridines (1,4-DHPs) was investigated by an integrated NMR, X-ray diffraction and molecular graphics study. 1 H- and 13 C-NMR showed that all the benzofuroxan derivatives exist in solution as tautomeric mixtures. Δ G ° and Δ G ∗ for 4′⇄7′ and 5′⇄7′ benzofuroxanyl tautomeric equilibria were determined for the benzofuroxan derivatives VI and VII . These figures are close to those observed for other substituted benzofuroxans known from literature including DHP derivatives. The conformational domain of all the compounds was analyzed, showing two sets of energetically accessible arrangements of the heterocyclic substructure with respect to C(4)H–DHP hydrogen, antiperiplanar and synperiplanar . Rotameric preference in solution around the C(4)–C(4′) bond in benzofurazanyl derivative IV was sought by normalized transient ΔNOE spectra using interatomic distances derived from AM1 energy minimized structures. A synperiplanar fraction of ca. 75% was calculated, in keeping with results obtained by Rovnyak for Nifedipine. Finally, the solid state preferred conformation was assessed by X-ray analysis for 5′-benzofurazanyl ( V ) and 5′(6′)-benzofuroxanyl ( VII ) derivatives. The latter in the solid state prefers the 5′-form ( VIIa ). The pentatomic ring systems always lie on the same side of the C(4)H–DHP hydrogen. This was also found to be the case for 4′-substituted derivatives and a large number of dihydropyridine derivatives.