T-type channels are important contributors to the initiation and the maintenance of chronic pain... more T-type channels are important contributors to the initiation and the maintenance of chronic pain states. Blocking T-type channels is therefore a possible therapeutic strategy for relieving pain. Here, we report the Cav3.2 T-type channel blocking action of a previously reported small organic molecule, KYS-05090S. This compound was able to reduce transiently expressed Cav3.2 currents with low micromolar affinity and mediated a hyperpolarizing shift in halfinactivationpotential.KYS-05090Swasthentestedinmodels of acute and neuropathic pain. KYS-05090S (10 μg/10 μl delivered intrathecally) significantly reduced acute pain induced by formalin in both the tonic and inflammatory phases. Its antinociceptive effect was not observed when delivered to Cav3.2 null-mice revealing a Cav3.2-dependent mechanism. KYS-05090S also reduced neuropathic pain in a model of partial sciatic nerve injury. Those results indicate that KYS05090S mediates a potent analgesic effect in inflammatory and neuropathic paint hrough T-type channel modulation, suggesting that its scaffold could be explored as a new class of analgesic compounds.
Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is a... more Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro-and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflam-matory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflam-matory events underlying disease.
A series of new 1-heteroaryl piperidinecarboxamide and piperazinylurea derivatives was synthesize... more A series of new 1-heteroaryl piperidinecarboxamide and piperazinylurea derivatives was synthesized and evaluated as TRPV1 modulators in a Ca 2þ channel assay in HEK-293 cells overexpressing the human recombinant TRPV1 channel. Structural variations in the putative key portions of the molecules afforded several compounds endowed with agonist and/or antagonist/desensitizing activity at low micromolar concentration. As promising examples from this series, the piperidine-3-carboxamide derivative 31 exerts agonist/desensitizing activity at low micromolar concentration, while piperazinylurea derivatives 39 and 41 act as antagonists with sub-micromolar potency.
Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involve... more Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease. Methods: We investigated the expression of PK2 in mice with experimental autoimmune encephalo-myelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activated against myelin antigen to explore the immune-modulating effects of this peptide in vitro. Results: Pk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demy-elination, and decreased the production of interferon (IFN)-g and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN-g and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen.
By using SLC-0111 (4-fluorophenylureido-benzenesulfonamide), a sulfonamide carbonic anhydrase (CA... more By using SLC-0111 (4-fluorophenylureido-benzenesulfonamide), a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials as an antitumor agent as lead molecule, a series of benzenesulfonamide derivatives incorporating ureido moieties was synthesized. The new compounds contain a 4-N-substituted piperazine fragment in which the ureido linker has been included, and were tested as inhibitors of the cytosolic human (h) hCA I and II isoforms, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. Depending on the substitution pattern at the piperazine ring, low nanomolar inhibitors were detected against all four isoforms, making the new class of sulfonamides of interest for various pharmacologic applications.
PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occu... more PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used i) in vitro, using human primary isolated cytotrophoblasts, and the extravillous trophoblast cell line (HTR-8/SVneo), ii) ex vivo, using human placental explants (n= 46 placentas), and iii) in vivo, using gravid wild type, PPARγ+/- and PPARγ -/- mice. Major processes of placental development, known to be controlled by PPARγsuch as trophoblast proliferation, migration and invasion were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. Both in human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγagonist, increased i) EG EGF secretion, ii) EG-VEGF and its receptors mRNA and protein expression, iii) placental vascularization, via PROKR1 and PROKR2, and iv) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ-/- mouse placentas, EG-VEGF levels were significantly decreased,supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγeffects during pregnancy, and bring new insights into the fine mechanism of trophoblast invasion.
Four positively charged compounds, previously shown to produce analgesic activity by interacting ... more Four positively charged compounds, previously shown to produce analgesic activity by interacting with prokineticin receptor or T-type calcium channels, were tested for their ability to inhibit capsaicin-induced elevation of intracellular Ca 2+ in HEK-293 cells stably transfected with the human recombinant TRPV1, with the goal of identifying novel TRPV1 open-pore inhibitors. KYS-05090 showed the highest potency as a TRPV1 antagonist, even higher than that of the open-pore triazine inhibitor 8aA. The latter showed quite remarkable agonist/desensitizer activity at the rat recombinant TRPM8 channel. The activity of KYS-05090 and the other compounds was selective because none of these compounds was able to modulate the rat TRPA1 channel. Open-pore inhibitors of TRPV1 may be a new class of multi-target analgesics with lesser side effects, such as loss of acute pain sensitivity and hyperthermia, than most TRPV1 antagonists developed so far.
Background: The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an a... more Background: The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an attractive target for the development of drugs used in the treatment of HIV-1 infection and acquired immune deficiency syndrome (AIDS). We have continued the search for novel anti-HIV-1 agents using the structure–activity relationships of the successful 1,3-disubstituted and 1,3,6-trisubstituted uracil-type HIV-1 RT inhibitors. Methods: A series of new triazine analogs were synthesized using an established method. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cyto-toxicity of the compounds was evaluated by assessing the viability of mock-infected cells. Results: Some of the compounds showed good-to-moderate activities against HIV-1, with half-maximal effective concentrations (EC 50) in the submicromolar range. In particular, a dihydro-1-(4-aminobenzyl)triazine analog showed satisfactory anti-HIV-1 activity with an EC 50 of 0.110 mM and a selectivity index (SI) of 909. Furthermore, molecular modeling analyses were performed to explore the major interactions between HIV-1 RT and potent inhibitors. These results may be important for further development of this class of compounds as anti-HIV-1 agents. Conclusion: The satisfactory anti-HIV-1 activity of triazine analogs may serve as the basis for further investigations of the behavior of this class of compounds against drug-resistant mutants.
A series of sulfamates were synthesized using as lead compound SLC-0111, a sulfonamide carbonic a... more A series of sulfamates were synthesized using as lead compound SLC-0111, a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials. The new derivatives incorporated ureido moieties as spacers between the benzene sulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor, but the urea moieties were part of a substituted piperazine ring system. The derivatives (and some of their phenol precursors) were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (K I s in the range of 1.0–94.4 nM), IX (K I s in the range of 0.91–36.9 nM), and XII (K I s in the range of 1.0–84.5 nM). The best substitution fragments at the piper-azine ring included the following moieties: 3-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 6-arylpyrimidine-2-yl.
The synthesis and antiproliferative activity of new benzimidazole derivatives bearing an hydrazon... more The synthesis and antiproliferative activity of new benzimidazole derivatives bearing an hydrazone mojety at the 2-position is described. The new N 1-(4-arylidene)-1H-benzo[d]imidazole-2-carbohydrazides were evaluated for their cytostatic activity toward the murine leukemia (L1210), human T-cell leukemia (CEM), human cervix carcinoma (HeLa) and human pancreas carcinoma cells (Mia Paca-2). A preliminary structure-activity relationship could be defined. Some of the compounds possess encouraging and consistent antiproliferative activity, having IC 50 values in the low micromolar range.
Different maleimide derivatives were synthesized and assayed for their in vitro activity on the s... more Different maleimide derivatives were synthesized and assayed for their in vitro activity on the soil inhabiting, plant-parasitic nematode Meloidogyne incognita, also known as root-knot nematode. The compounds maleimide, N-ethylmaleimide, N-isopropylmaleimide, and N-isobutylmaleimide showed the strongest nematicidal activity on the second stage juveniles of the root-knot nematode with EC 50/72h values of 2.6 ± 1.3, 5.1 ± 3.4, 16.2 ± 5.4, and 19.0 ± 9.0 mg/L, respectively. We also determined the nematicidal activity of copper sulfate, finding an EC 50 value of 48.6 ± 29.8 mg/L. When maleimide at 1 mg/L was tested in combination with copper sulfate at 50 mg/L, we observed 100% mortality of the nematodes. We performed a GC-MS metabolomics analysis after treating nematodes with maleimide at 8 mg/L for 24 h. This analysis revealed altered fatty acids and diglyceride metabolites such as oleic acid, palmitic acid, and 1-monopalmitin. Our results suggest that maleimide may be used as a new interesting building block for developing new nematicides in combination with copper salts.
A series of aryl hydrazones were synthesized and in vitro assayed for their activity on the root-... more A series of aryl hydrazones were synthesized and in vitro assayed for their activity on the root-knot nematode Meloidogyne incognita. The phenylhydrazones of thiophene-2-carboxyaldehyde 5, 3-methyl-2-thiophenecarboxyaldehyde, 6, and salicylaldehyde, 2, were the most potent with EC 50/48h values of 16.6 ± 2.2, 23.2 ± 2.7, and 24.3 ± 1.4 mg/L, respectively. A GC-MS metabolomics analysis, after in vitro nematode treatment with hydrazone 6 at 100 mg/L for 12 h, revealed elevated levels of fatty acids such as lauric acid, stearic acid, 2-octenoic acid, and palmitic acid. Whereas control samples showed the highest levels of monoacylglycerols such as monostearin and 2-monostearin, surprisingly, 2 h after treatment with hydrazone 6, nematodes excreted 3 times the levels of ammonia eliminated in the same conditions by controls. Thus, phenylhydrazones may represent a good scaffold in the discovery and synthesis of new nematicidal compounds, and a metabolomics approach may be helpful in understanding their mechanisms of toxicity and mode of action.
The 3,5-diaminoisothiazole derivatives 23-42 were synthesized in excellent yields by oxidative cy... more The 3,5-diaminoisothiazole derivatives 23-42 were synthesized in excellent yields by oxidative cyclization of 3-amino-3-(dialkylamino)propenethioamide derivatives. These intermediates and the isothiazole derivatives were tested in vitro for their antimicrobial activity.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The 3,5-diaminoisothiazole derivatives 23-42 were synthesized in excellent yields by oxidative cy... more The 3,5-diaminoisothiazole derivatives 23-42 were synthesized in excellent yields by oxidative cyclization of 3-amino-3-(dialkylamino)propenethioamide derivatives. These intermediates and the isothiazole derivatives were tested in vitro for their antimicrobial activity.
T-type channels are important contributors to the initiation and the maintenance of chronic pain... more T-type channels are important contributors to the initiation and the maintenance of chronic pain states. Blocking T-type channels is therefore a possible therapeutic strategy for relieving pain. Here, we report the Cav3.2 T-type channel blocking action of a previously reported small organic molecule, KYS-05090S. This compound was able to reduce transiently expressed Cav3.2 currents with low micromolar affinity and mediated a hyperpolarizing shift in halfinactivationpotential.KYS-05090Swasthentestedinmodels of acute and neuropathic pain. KYS-05090S (10 μg/10 μl delivered intrathecally) significantly reduced acute pain induced by formalin in both the tonic and inflammatory phases. Its antinociceptive effect was not observed when delivered to Cav3.2 null-mice revealing a Cav3.2-dependent mechanism. KYS-05090S also reduced neuropathic pain in a model of partial sciatic nerve injury. Those results indicate that KYS05090S mediates a potent analgesic effect in inflammatory and neuropathic paint hrough T-type channel modulation, suggesting that its scaffold could be explored as a new class of analgesic compounds.
Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is a... more Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro-and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflam-matory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflam-matory events underlying disease.
A series of new 1-heteroaryl piperidinecarboxamide and piperazinylurea derivatives was synthesize... more A series of new 1-heteroaryl piperidinecarboxamide and piperazinylurea derivatives was synthesized and evaluated as TRPV1 modulators in a Ca 2þ channel assay in HEK-293 cells overexpressing the human recombinant TRPV1 channel. Structural variations in the putative key portions of the molecules afforded several compounds endowed with agonist and/or antagonist/desensitizing activity at low micromolar concentration. As promising examples from this series, the piperidine-3-carboxamide derivative 31 exerts agonist/desensitizing activity at low micromolar concentration, while piperazinylurea derivatives 39 and 41 act as antagonists with sub-micromolar potency.
Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involve... more Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease. Methods: We investigated the expression of PK2 in mice with experimental autoimmune encephalo-myelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activated against myelin antigen to explore the immune-modulating effects of this peptide in vitro. Results: Pk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demy-elination, and decreased the production of interferon (IFN)-g and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN-g and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen.
By using SLC-0111 (4-fluorophenylureido-benzenesulfonamide), a sulfonamide carbonic anhydrase (CA... more By using SLC-0111 (4-fluorophenylureido-benzenesulfonamide), a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials as an antitumor agent as lead molecule, a series of benzenesulfonamide derivatives incorporating ureido moieties was synthesized. The new compounds contain a 4-N-substituted piperazine fragment in which the ureido linker has been included, and were tested as inhibitors of the cytosolic human (h) hCA I and II isoforms, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. Depending on the substitution pattern at the piperazine ring, low nanomolar inhibitors were detected against all four isoforms, making the new class of sulfonamides of interest for various pharmacologic applications.
PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occu... more PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used i) in vitro, using human primary isolated cytotrophoblasts, and the extravillous trophoblast cell line (HTR-8/SVneo), ii) ex vivo, using human placental explants (n= 46 placentas), and iii) in vivo, using gravid wild type, PPARγ+/- and PPARγ -/- mice. Major processes of placental development, known to be controlled by PPARγsuch as trophoblast proliferation, migration and invasion were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. Both in human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγagonist, increased i) EG EGF secretion, ii) EG-VEGF and its receptors mRNA and protein expression, iii) placental vascularization, via PROKR1 and PROKR2, and iv) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ-/- mouse placentas, EG-VEGF levels were significantly decreased,supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγeffects during pregnancy, and bring new insights into the fine mechanism of trophoblast invasion.
Four positively charged compounds, previously shown to produce analgesic activity by interacting ... more Four positively charged compounds, previously shown to produce analgesic activity by interacting with prokineticin receptor or T-type calcium channels, were tested for their ability to inhibit capsaicin-induced elevation of intracellular Ca 2+ in HEK-293 cells stably transfected with the human recombinant TRPV1, with the goal of identifying novel TRPV1 open-pore inhibitors. KYS-05090 showed the highest potency as a TRPV1 antagonist, even higher than that of the open-pore triazine inhibitor 8aA. The latter showed quite remarkable agonist/desensitizer activity at the rat recombinant TRPM8 channel. The activity of KYS-05090 and the other compounds was selective because none of these compounds was able to modulate the rat TRPA1 channel. Open-pore inhibitors of TRPV1 may be a new class of multi-target analgesics with lesser side effects, such as loss of acute pain sensitivity and hyperthermia, than most TRPV1 antagonists developed so far.
Background: The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an a... more Background: The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an attractive target for the development of drugs used in the treatment of HIV-1 infection and acquired immune deficiency syndrome (AIDS). We have continued the search for novel anti-HIV-1 agents using the structure–activity relationships of the successful 1,3-disubstituted and 1,3,6-trisubstituted uracil-type HIV-1 RT inhibitors. Methods: A series of new triazine analogs were synthesized using an established method. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cyto-toxicity of the compounds was evaluated by assessing the viability of mock-infected cells. Results: Some of the compounds showed good-to-moderate activities against HIV-1, with half-maximal effective concentrations (EC 50) in the submicromolar range. In particular, a dihydro-1-(4-aminobenzyl)triazine analog showed satisfactory anti-HIV-1 activity with an EC 50 of 0.110 mM and a selectivity index (SI) of 909. Furthermore, molecular modeling analyses were performed to explore the major interactions between HIV-1 RT and potent inhibitors. These results may be important for further development of this class of compounds as anti-HIV-1 agents. Conclusion: The satisfactory anti-HIV-1 activity of triazine analogs may serve as the basis for further investigations of the behavior of this class of compounds against drug-resistant mutants.
A series of sulfamates were synthesized using as lead compound SLC-0111, a sulfonamide carbonic a... more A series of sulfamates were synthesized using as lead compound SLC-0111, a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials. The new derivatives incorporated ureido moieties as spacers between the benzene sulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor, but the urea moieties were part of a substituted piperazine ring system. The derivatives (and some of their phenol precursors) were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (K I s in the range of 1.0–94.4 nM), IX (K I s in the range of 0.91–36.9 nM), and XII (K I s in the range of 1.0–84.5 nM). The best substitution fragments at the piper-azine ring included the following moieties: 3-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 6-arylpyrimidine-2-yl.
The synthesis and antiproliferative activity of new benzimidazole derivatives bearing an hydrazon... more The synthesis and antiproliferative activity of new benzimidazole derivatives bearing an hydrazone mojety at the 2-position is described. The new N 1-(4-arylidene)-1H-benzo[d]imidazole-2-carbohydrazides were evaluated for their cytostatic activity toward the murine leukemia (L1210), human T-cell leukemia (CEM), human cervix carcinoma (HeLa) and human pancreas carcinoma cells (Mia Paca-2). A preliminary structure-activity relationship could be defined. Some of the compounds possess encouraging and consistent antiproliferative activity, having IC 50 values in the low micromolar range.
Different maleimide derivatives were synthesized and assayed for their in vitro activity on the s... more Different maleimide derivatives were synthesized and assayed for their in vitro activity on the soil inhabiting, plant-parasitic nematode Meloidogyne incognita, also known as root-knot nematode. The compounds maleimide, N-ethylmaleimide, N-isopropylmaleimide, and N-isobutylmaleimide showed the strongest nematicidal activity on the second stage juveniles of the root-knot nematode with EC 50/72h values of 2.6 ± 1.3, 5.1 ± 3.4, 16.2 ± 5.4, and 19.0 ± 9.0 mg/L, respectively. We also determined the nematicidal activity of copper sulfate, finding an EC 50 value of 48.6 ± 29.8 mg/L. When maleimide at 1 mg/L was tested in combination with copper sulfate at 50 mg/L, we observed 100% mortality of the nematodes. We performed a GC-MS metabolomics analysis after treating nematodes with maleimide at 8 mg/L for 24 h. This analysis revealed altered fatty acids and diglyceride metabolites such as oleic acid, palmitic acid, and 1-monopalmitin. Our results suggest that maleimide may be used as a new interesting building block for developing new nematicides in combination with copper salts.
A series of aryl hydrazones were synthesized and in vitro assayed for their activity on the root-... more A series of aryl hydrazones were synthesized and in vitro assayed for their activity on the root-knot nematode Meloidogyne incognita. The phenylhydrazones of thiophene-2-carboxyaldehyde 5, 3-methyl-2-thiophenecarboxyaldehyde, 6, and salicylaldehyde, 2, were the most potent with EC 50/48h values of 16.6 ± 2.2, 23.2 ± 2.7, and 24.3 ± 1.4 mg/L, respectively. A GC-MS metabolomics analysis, after in vitro nematode treatment with hydrazone 6 at 100 mg/L for 12 h, revealed elevated levels of fatty acids such as lauric acid, stearic acid, 2-octenoic acid, and palmitic acid. Whereas control samples showed the highest levels of monoacylglycerols such as monostearin and 2-monostearin, surprisingly, 2 h after treatment with hydrazone 6, nematodes excreted 3 times the levels of ammonia eliminated in the same conditions by controls. Thus, phenylhydrazones may represent a good scaffold in the discovery and synthesis of new nematicidal compounds, and a metabolomics approach may be helpful in understanding their mechanisms of toxicity and mode of action.
The 3,5-diaminoisothiazole derivatives 23-42 were synthesized in excellent yields by oxidative cy... more The 3,5-diaminoisothiazole derivatives 23-42 were synthesized in excellent yields by oxidative cyclization of 3-amino-3-(dialkylamino)propenethioamide derivatives. These intermediates and the isothiazole derivatives were tested in vitro for their antimicrobial activity.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The 3,5-diaminoisothiazole derivatives 23-42 were synthesized in excellent yields by oxidative cy... more The 3,5-diaminoisothiazole derivatives 23-42 were synthesized in excellent yields by oxidative cyclization of 3-amino-3-(dialkylamino)propenethioamide derivatives. These intermediates and the isothiazole derivatives were tested in vitro for their antimicrobial activity.
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