The phthalimide analogues N-3-hydroxypropylphthalimide and N-carboxymethyl-3-nitrophthalimide exhibit activity in experimental models of inflammatory and neuropathic pain.

BACKGROUND: Phthalimide analogues devoid of the glutarimide moiety exhibit multiple biological activities, thus making them candidates for the treatment of patients with different diseases, including those with inflammatory and painful disorders. In the present study, the activities of five phthalimide analogues devoid of the glutarimide moiety (N-hydroxyphthalimide, N-hydroxymethylphthalimide, N-3-hydroxypropylphthalimide, N-carboxy-3-methylphthalimide, N-carboxymethyl-3-nitrophthalimide) were evaluated in experimental models of acute and chronic inflammatory and neuropathic pain. METHODS: The phthalimide analogues were administered per os (po) in Swiss mice or Wistar rats. Nociceptive response induced by formaldehyde and mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve or intraplantar (ipl) injection of complete Freund's adjuvant (CFA) were used as experimental models of pain. RESULTS: N-carboxymethyl-3-nitrophthalimide (700 mg/kg, -1 h) inhibited the second phase of the nociceptive response induced by the intraplantar injection of formaldehyde in mice. N-3-hidroxypropylphthalimide (546 mg/kg, -1 h) inhibited both phases of the nociceptive response induced by formaldehyde. Treatment of rats with N-carboxymethyl-3-nitrophthalimide (700 mg/kg) or N-3-hydroxypropylphthalimide (546 mg/kg) inhibited the mechanical allodynia induced by CCI of the sciatic nerve or ipl injection of CFA in rats. Intraperitoneal administration of the opioid antagonist naltrexone (10 mg/kg, -1.5 h) attenuated the antinociceptive activity of N-carboxymethyl-3-nitrophthalimide (700 mg/kg) in the model of nociceptive response induced by formaldehyde. CONCLUSIONS: N-3-hydroxypropylphthalimide and N-carboxymethyl-3-nitrophthalimide, two phthalimide analogues devoid of the glutarimide moiety, exhibited activities in different experimental models of pain, including models of chronic inflammatory and neuropathic pain.

Exploring the structural landscape of 2-(thiophen-2-yl)-1,3-benzothiazole: high-Z' packing polymorphism and cocrystallization with calix[4]tube.

We report here for the first time a cocrystal of the so-called neutral calix[4]tube, which is two tail-to-tail-arranged and partially deprotonated tetrakis(carboxymethoxy)calix[4]arenes, including three sodium ions, with 2-(thiophen-2-yl)-1,3-benzothiazole, namely trisodium bis(carboxymethoxy)bis(carboxylatomethoxy)calix[4]arene tris(carboxymethoxy)(carboxylatomethoxy)calix[4]arene-2-(thiophen-2-yl)-1,3-benzothiazole-dimethyl sulfoxide-water (1/1/2/2), 3Na+·C36H30O122-·C36H31O12-·C11H7NS2·2C2H6OS·2H2O, which provides a new approach into the host-guest chemistry of inclusion complexes. Three packing polymorphs of the same benzothiazole with high Z' (one with Z' = 8 and two with Z' = 4) were also discovered in the course of our desired cocrystallization. The inspection of these polymorphs and a previously known polymorph with Z' = 2 revealed that Z' increases as the strength of intermolecular contacts decreases. Also, these results expand the frontier of invoking calixarenes as a host for nonsolvent small molecules, besides providing knowledge on the rare formation of high-Z' packing polymorphs of simple molecules, such as the target benzothiazole.

2-Phthalimidethanol and 2-phthalimidethyl nitrate inhibit mechanical allodynia, neutrophil recruitment and cytokine and chemokine production in a murine model of articular inflammation.

BACKGROUND: Phthalimide analogs have been shown to exhibit anti-inflammatory, analgesic and immunomodulatory activities in different preclinical assays. This study aimed to investigate the potential role of 2-phthalimidethanol (PTD-OH) and 2-phthalimidethyl nitrate (PTD-NO) in a murine model of antigen-induced articular inflammation. METHODS: Articular inflammation was induced by intra-articular injection of methylated bovine serum albumin (mBSA) in the knee joint of immunized male C57BL/6J mice. The animals were pre-treated with PTD-OH or PTD-NO (500mg/kg, per os, - 1h). Nociceptive threshold was measured using an electronic von Frey apparatus. The total number of leukocytes in the synovial cavity was determined. Concentrations of tumor necrosis factor (TNF)-α and CXCL-1 and myeloperoxidase (MPO) activity were determined in periarticular tissue. RESULTS: Both PTD-OH and PTD-NO inhibited at similar extent the mechanical allodynia, neutrophil recruitment to the synovial cavity and periarticular tissue and TNF-α and CXCL-1 production induced by intra-articular challenge with mBSA in immunized mice. CONCLUSIONS: PTD-OH and PTD-NO exhibit a marked activity in a murine model of antigen-induced articular inflammation in immunized animals. These results reinforce the interest in the investigation of phthalimide analogs devoid of the glutarimide ring as candidates to analgesic and anti-inflammatory drugs.

Nicorandil inhibits neutrophil recruitment in carrageenan-induced experimental pleurisy in mice.

Nicorandil is a drug characterized by the coupling of a nitric oxide (NO) donor to nicotinamide. We have previously demonstrated that nicotinamide exhibits activity in different models of pain and inflammation. Now, we investigated the effects induced by per os (p.o.) administration of nicorandil (25, 50 or 100mg/Kg) on neutrophil recruitment in a carrageenan-induced model of pleurisy in mice. Effects induced by nicorandil (100mg/kg) were compared with those induced by equimolar doses of nicotinamide (58mg/kg) and N-(2-hydroxyethyl)-nicotinamide (NHN; 79mg/kg). We also investigated whether effects on the production of inflammatory mediators play a role in the activity of nicorandil. P.o. nicorandil, 0.5h before and 1h after the i.pl. injection of carrageenan, reduced neutrophil recruitment. However, equimolar doses of nicotinamide or NHN failed to induce such effect. Single treatment (previous or late) with nicorandil (100mg/Kg, p.o.) also reduced neutrophils recruitment, although to a lesser extent when compared to the double treatment. Nicorandil reduced the concentrations of interleukin-1ß, CXCL-1 and prostaglandin E2 in the pleural exudate. Concluding, we demonstrated the activity of nicorandil in a model of pleurisy induced by carrageenan. This activity was characterized by reduction of the neutrophil accumulation and inhibition of production of inflammatory mediators. The effects induced by nicorandil on the leukocytes recruitment and production of inflammatory mediators contribute to a better understanding of its clinical benefits and indicate that these benefits may be due to its vasodilating and anti-inflammatory activities.

Opioid pathways activation mediates the activity of nicorandil in experimental models of nociceptive and inflammatory pain.

We have previously demonstrated that nicorandil inhibits the second phase of the nociceptive response induced by formaldehyde. In the present study, we evaluated the effects induced by nicorandil in other models of nociceptive and inflammatory pain in mice and also whether opioid pathways activation mediates its activity. As we have previously demonstrated, per os (p.o.) administration of nicorandil (50, 100 or 150mg/kg; -1h) inhibited the second phase of the nociceptive response induced by intraplantar (i.pl.) injection of formaldehyde. Nicorandil (50, 100 or 150mg/kg; p.o., -1h) also exhibited activity in models of inflammatory pain induced by i.pl. injection of carrageenan (300µg) and nociceptive pain induced by exposure to noxious heat (50°C). Intraperitoneal (i.p.) administration of the opioid antagonist naltrexone (1, 5 or 10mg/kg, -30min) attenuated or abolished the antinociceptive activity of nicorandil (100mg/kg, p.o.) in the three experimental pain models. In conclusion, we demonstrate that nicorandil exhibits activity in different models of nociceptive and inflammatory pain. The demonstration that the antinociceptive effect induced by nicorandil is markedly attenuated by an opioid antagonist provides solid information about an important mechanism mediating the activity of this antianginal drug. Altogether, our data suggest that the clinical pain relief induced by nicorandil in heart ischemic conditions may result from both vasodilation and intrinsic analgesic activity.

Activities of 2-phthalimidethyl nitrate and 2-phthalimidethanol in the models of nociceptive response and edema induced by formaldehyde in mice and preliminary investigation of the underlying mechanisms.

The activities of 2-phthalimidethyl nitrate (PTD-NO) and 2-phthalimidethanol (PTD-OH) were recently demonstrated in models of pain and inflammation. We expanded our investigation by evaluating their activities in models of nociceptive and inflammatory pain and inflammatory edema, the preliminary pharmacokinetic parameter for PTD-NO and the role of opioid and cannabinoid pathways in the activity of analogs. Per os (p.o.) administration of PTD-NO or PTD-OH, 1h before intraplantar injection of formaldehyde, inhibited both phases of the nociceptive response (500 and 750 mg/kg) and paw edema (125, 250, 500 and 750 mg/kg). After p.o. administration of PTD-NO, peak plasma concentrations of PTD-NO and PTD-OH were found 0.92 and 1.13 h, respectively. The plasma concentrations of PTD-NO were higher than those of PTD-OH. Intraperitoneal (i.p.) administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists (4 or 8 mg/kg, -30 min) or opioid antagonist naltrexone (5 or 10mg/kg, -30 min) did not affect the antinociceptive activities of the analogs. AM251 (8 mg/kg, i.p., -30 min) attenuated the antiedematogenic activity of both analogs, while naltrexone (10mg/kg, i.p., -30 min) only attenuated the antiedematogenic activity of PTD-NO. The antiedematogenic activities of both analogs were not affected by the CB2 cannabinoid antagonist AM630 (4 or 8 mg/kg, i.p., -30 min). Concluding, we expanded the knowledge on the activities of PTD-NO and PTD-OH by showing that these phthalimide analogs also exhibit marked activity in models of nociceptive and inflammatory pain and inflammatory edema. Opioid and cannabinoid mechanisms partially mediate the anti-inflammatory, but not the antinociceptive activity.

An overview on the potential of natural products as ureases inhibitors: A review.

Ureases, enzymes that catalyze urea hydrolysis, have received considerable attention for their impact on living organisms' health and life quality. On the one hand, the persistence of urease activity in human and animal cells can be the cause of some diseases and pathogen infections. On the other hand, food production can be negatively affected by ureases of soil microbiota that, in turn, lead to losses of nitrogenous nutrients in fields supplemented with urea as fertilizer. In this context, nature has proven to be a rich resource of natural products bearing a variety of scaffolds that decrease the ureolytic activity of ureases from different organisms. Therefore, this work compiles the state-of-the-art researches focused on the potential of plant natural products (present in extracts or as pure compounds) as urease inhibitors of clinical and/or agricultural interests. Emphasis is given to ureases of Helicobacter pylori, Canavalia ensiformis and soil microbiota although the active site of this class of hydrolases is conserved among living organisms.

Activities of 2-phthalimidethanol and 2-phthalimidethyl nitrate, phthalimide analogs devoid of the glutarimide moiety, in experimental models of inflammatory pain and edema.

The reintroduction of thalidomide in the pharmacotherapy greatly stimulated the interest in the synthesis and pharmacological evaluation of phthalimide analogs with new and improved activities and also greater safety. In the present study, we evaluated the activities of two phthalimide analogs devoid of the glutarimide ring, namely 2-phthalimidethanol (PTD-OH) and 2-phthalimidethyl nitrate (PTD-NO), in experimental models of inflammatory pain and edema in male C57BL/6J mice. Intraplantar (i.pl.) injection of carrageenan (300 µg) induced mechanical allodynia and this response was inhibited by previous per os (p.o.) administration of PTD-OH and PTD-NO (750 mg/kg) and also by thalidomide (500 or 750 mg/kg). The edema induced by carrageenan was also inhibited by previous p.o. administration of PTD-OH (500 and 750 mg/kg) and PTD-NO (125, 250, 500 or 750 mg/kg), but not by thalidomide. Carrageenan increased tumor necrosis factor (TNF)-α and CXCL1 concentrations and also the number of neutrophils in the paw tissue. Previous p.o. administration of PTD-NO (500 mg/kg) reduced all the parameters, while PTD-OH (500 mg/kg) reduced only the accumulation of neutrophils. Thalidomide, on the other hand, was devoid of effect on these biochemical parameters. Plasma concentrations of nitrite were increased after p.o. administration of the phthalimide analog coupled to a NO donor, PTD-NO (500 mg/kg), but not after administration of PTD-OH or thalidomide. In conclusion, our results show that small molecules, structurally much simpler than thalidomide or many of its analogs under investigation, exhibit similar activities in experimental models of pain and inflammation. Finally, as there is evidence that the glutarimide moiety contributes to the teratogenic effect of many thalidomide analogs, our results indicate that phthalimide analogs devoid of this functional group could represent a new class of analgesic and anti-inflammatory candidates with potential greater safety.

Synthesis, antinociceptive activity and pharmacokinetic profiles of nicorandil and its isomers.

Nicorandil (N-(2-hydroxyethyl)nicotinamide nitrate) is an antianginal drug, which activates guanylyl cyclase and opens the ATP-dependent K(+) channels, actions that have been suggested to mediate its vasodilator activity. We synthesized nicorandil and its two isomers, which vary in the positions of the side chain containing the nitric oxide (NO) donor, and also their corresponding denitrated metabolites. The activities of these compounds were evaluated in an experimental model of pain in mice. Pharmacokinetic parameters of nicorandil and its isomers, as well as the plasma concentrations of the corresponding denitrated metabolites and also nicotinamide and nitrite were determined. Nicorandil exhibited the highest antinociceptive activity, while the ortho-isomer was the least active. Nicorandil and para-nicorandil, which induced higher plasma concentrations of nitrite, exhibited higher antinociceptive activity, which suggests that the release of NO may mediate this activity.

Assessment of leishmanicidal and trypanocidal activities of aliphatic diamine derivatives.

Leishmanicidal and trypanocidal activity of seventeen lipophilic diamines was evaluated in vitro against Leishmania braziliensis, L. chagasi, and Trypanosoma cruzi. Twelve compounds presented anti-Leishmania and six showed anti-T. cruzi amastigote activity. Compound 14 (N-tetradecyl-1,4-butanediamine) was the most active against both L. braziliensis (IC50  = 2.6 µm) and L. chagasi (IC50  = 3.0 µm) which showed a selectivity index (SI) >100. N-decyl-1,6-hexanediamine (compound 9) presented an IC50  = 1.6 µm and SI >187 and was over six times more potent than the reference drug benznidazole against T. cruzi. Treatment of infected or uninfected macrophages with compounds 9 and 14 did not induce significant TNFα and NO production. Four compounds (15, 16, 22, and 23) inhibited 78.9%, 77.7%, 83.7%, and 70.1% of rTRLb activity, respectively, and compound 23 inhibited 73.3% of rTRTc activity at 100 µm. A concentration-dependent effect on mitochondrial membrane depolarization was observed in T. cruzi epimastigotes treated with compound 9, suggesting this mechanism may be involved in the trypanocidal effect. On the contrary, in L. braziliensis promastigotes treated with compound 14, no mitochondrial depolarization was observed. Our results demonstrate that N-decyl-1,6-hexanediamine and N-tetradecyl-1,4-butanediamine are promising molecules for the development of novel leading compounds against T. cruzi and Leishmania spp., particularly given a possible alternative mechanism of action.

Activity of nicorandil, a nicotinamide derivative with a nitrate group, in the experimental model of pain induced by formaldehyde in mice.

Nicorandil (2-nicotinamide ethyl nitrate), an antianginal drug characterized by the coupling of nicotinamide with a nitric oxide (NO) donor, activates guanylyl cyclase and opens ATP-dependent K(+) channels. In the present study, we investigated the effects induced by per os (p.o.) administration of nicorandil (12.5, 25 or 50 mg/kg) or equimolar doses (corresponding to the highest dose of nicorandil) of N-(2-hydroxyethyl) nicotinamide (NHN), its main metabolite, or nicotinamide in the model of nociceptive response induced by formaldehyde in mice. Nicorandil, but not NHN or nicotinamide, inhibited the second phase of the nociceptive response. This activity was observed when nicorandil was administered between 30 and 120 min before the injection of formaldehyde. Ipsilateral intraplantar injection of nicorandil (125, 250 or 500 µg/paw) did not inhibit the nociceptive response. After p.o. administration of nicorandil (50 mg/kg), peak plasma concentrations of this compound and NHN were observed 0.63 and 4 h later, respectively. Nicotinamide concentrations were not increased after administration of nicorandil. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 or 2 mg/kg), a guanylyl cyclase inhibitor, partially attenuated the antinociceptive activity of nicorandil. However, this activity was not changed by glibenclamide (30 or 60 mg/kg), an inhibitor of ATP-dependent K(+) channels. In conclusion, we demonstrated the antinociceptive activity of nicorandil in a model of pain that exhibits both a nociceptive and an inflammatory profile. This activity is not mediated by nicotinamide or NHN. The coupling of an NO-donor to nicotinamide results in a compound with an increased potency. The NO-cGMP pathway, but not ATP-dependent K(+) channels, partially mediates the antinociceptive activity of nicorandil.

N-(2-Nitro-oxyeth-yl)picolinamide.

In the title mol-ecule, C(8)H(9)N(3)O(4), the amide group is involved in the formation of an intra-molecular N-H⋯N hydrogen bond. In the crystal, mol-ecules related by translation along the a axis are linked into chains via weak inter-molecular C-H⋯O inter-actions.

Synthesis and antitubercular evaluation of new fluoroquinolone derivatives coupled with carbohydrates.

We describe in this work the synthesis of nine new fluoroquinolone derivatives based on modifications at the C-7 position of the known fluoroquinolones cipro-, gati-, and moxifloxacin, as well as their antitubercular evaluation. The synthesis of these new analogues was improved using microwave irradiation, providing several advantages such as better yields and shorter reaction times, in comparison with classical reaction conditions. Derivatives 4, 5, and 7 exhibited promising antitubercular activities.

Preparation and antitubercular activity of lipophilic diamines and amino alcohols.

A series of diamines and amino alcohols derived from 1-dodecanol, 1-tetradecanol, 1,2-dodecanediol and 1,2-tetradecanediol were synthesized and tested for their antitubercular activity. Compounds 3, 8 and 9 were found to be the most active (MIC of 6.25 microg/mL). Nine other compounds displayed activity against Mycobacterium tuberculosis, with a MIC of 12.5 microg/mL.

Preparation and antitubercular activity of lipophilic diamines and amino alcohols

A series of diamines and amino alcohols derived from 1-dodecanol, 1-tetradecanol, 1,2-dodecanediol and 1,2-tetradecanediol were synthesized and tested for their antitubercular activity. Compounds 3, 8 and 9 were found to be the most active (MIC of 6.25 µg/mL). Nine other compounds displayed activity against Mycobacterium tuberculosis, with a MIC of 12.5 µg/mL.

Preparation and antitubercular activities of alkylated amino alcohols and their glycosylated derivatives.

A series of N- and C-alkylated amino alcohols and of their protected galactopyranosyl derivatives was synthesized and evaluated for antitubercular activity. Five of these compounds displayed good activity, with a MIC below 12.5mug/mL. The presence of the carbohydrate slightly affected the antibacterial activity.