Cholesteryl ester transfer protein (CETP) inhibitors based on cyclic urea, bicyclic urea and bicyclic sulfamide cores.

Cholesteryl ester transfer protein (CETP) inhibitors reduce the transfer of cholesteryl esters from the high-density lipoprotein (HDL-C) to apolipoprotein such as VLDL/LDL, with exchange of triglycerides. Thus, this inhibition increases the HDL-C levels, which is believed to lower the risk for heart disease and stroke. We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described.

Quinoline-sulfamoyl carbamates/sulfamide derivatives: Synthesis, cytotoxicity, carbonic anhydrase activity, and molecular modelling studies.

Carbonic anhydrase (CA) IX, and XII isoforms are known to be highly expressed in various human tissues and malignancies. CA IX is a prominent target for some cancers because it is overexpressed in hypoxic tumors and this overexpression leads to poor prognosis. Novel twenty-seven compounds in two series (sulfamoylcarbamate-based quinoline (2a-2o) and sulfamide-based quinoline (3a-3l)) were synthesized and characterized by means of IR, NMR, and mass spectra. Their inhibitory activities were evaluated against CA I, CA II, CA IX, and CA XII isoforms. 2-Phenylpropyl (N-(quinolin-8-yl)sulfamoyl)carbamate (2m) exhibited the highest hCA IX inhibition with the Ki of 0.5 µM. In addition, cytotoxic effects of the synthesized compounds on human colorectal adenocarcinoma (HT-29; HTB-38), human breast adenocarcinoma (MCF7; HTB-22), human prostate adenocarcinoma (PC3; CRL-1435) and human healthy skin fibroblast (CCD-986Sk; CRL-1947) cell lines were examined. The cytotoxicity results showed that 2j, 3a, 3e, 3f are most active compounds in all cell lines (HT-29, MCF7, PC3, and CCD-986Sk).

Inhibition Profiles of Some Symmetric Sulfamides Derived from Phenethylamines on Human Carbonic Anhydrase I, and II Isoenzymes.

In this work, the inhibitory effect of some symmetric sulfamides derived from phenethylamines were determined against human carbonic anhydrase (hCA) I, and II isoenzymes, and compared with standard compound acetazolamide. IC50 values were obtained from the Enzyme activity (%)-[Symmetric sulfamides] graphs. Also, Ki values were calculated from the Lineweaver-Burk graphs. Some symmetric sulfamides compounds (11-18) demonstrated excellent inhibition effects against hCA I, and II isoenzymes. These compounds demonstrated effective inhibitory profiles with IC50 values in ranging from 21.66-28.88 nM against hCA I, 14.44-30.13 nM against hCA II. Among these compounds, the best Ki value for hCA I (Ki : 8.34±1.60 nM) and hCA II (Ki : 16.40±1.00 nM) is compound number 11. Besides, the IC50 value of acetazolamide used as a standard was determined as hCA I, hCA II 57.75 nM, 49.50 nM, respectively. Moreover, in silico ADME-Tox study showed that all synthesized compounds (11-18) had good oral bioavailability in light of Jorgensen's rule of three, and of Lipinski's rule of five.

7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a "Cut and Glue" Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors.

Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.

Novel tribenzylaminobenzolsulphonylimine based on their pyrazine and pyridazines: Synthesis, characterization, antidiabetic, anticancer, anticholinergic, and molecular docking studies.

A new method of obtaining multifunctional pyrazoles by the reaction of 1,3-dipolar addition of tribenzylsulfonyliminochloride to polarophiles has been developed. This imine is obtained by reacting tribenzylamine with N-chlorobenzene sulfamide (chloramine-B). Regardless of the structure and composition of polarophiles, the cyclization reaction takes place in the presence of alkali in 6-8 h of boiling, which proves the activation of the methylene groups of tribenzylamine using the electron-withdrawing sulfonamide group. These novel derivatives were effective inhibitors of the α-glycosidase, butyrylcholinesterase (BChE), and acetylcholinesterase enzymes (AChE) with Ki values in the range of 0.45 ±â€¯0.08-1.24 ±â€¯0.27 µM for α-glycosidase, 6.04 ±â€¯0.95-11.61 ±â€¯2.84 µM for BChE, and 2.04 ±â€¯0.24-4.23 ±â€¯1.02 µM for AChE, respectively. The biological activities of the studied molecules against enzyme molecules were investigated by molecular docking calculations. The enzymes studied were AChE for ID 4M0E, BChE for ID 5NN0 BChE, and α-Glycosidase for ID 1XSI (α-Gly) respectively.

Tuning the Anomeric Effect in Sulfamide with Superacids.

This study shows that the anomeric effect (negative hyperconjugation) that arises in sulfamide, as a result of the relatively short S-N bonds, can be tuned by the utilization of superacidic media. Sulfamide was reacted in binary superacidic systems XF/MF5 (M=As, Sb; X=H, D) and HF/BF3 . The colorless salts formed, [X2 NSO2 NX3 ]+ [MF6 ]- and [H2 NSO2 NH3 ]+ [BF4 ]- were characterized by low-temperature vibrational spectroscopy. In the case of [H2 NSO2 NH3 ]+ [BF4 ]- , a single crystal X-ray diffraction study was performed. The salt crystallizes in the monoclinic space group P21 /c with four formula units per unit cell. An exclusive N,N'-diprotonation was observed in the superacidic system HF/SbF5 when using several equivalents of the Lewis acid. Low-temperature vibrational spectra as well as a single-crystal X-ray structure of [H3 NSO2 NH3 ]2+ 2 [SbF6 ]- ⋅2 HF are reported. The salt crystallizes in the orthorhombic space group Pna21 with four formula units per unit cell. Upon mono- or diprotonation of sulfamide, remarkable structural changes of the sulfur-nitrogen bond lengths were observed. Herein, these changes are discussed together with quantum chemical calculations.

Synthesis of novel substituted pyrimidine derivatives bearing a sulfamide group and their in vitro cancer growth inhibition activity.

The synthesis of two series of novel substituted pyrimidine derivatives bearing a sulfamide group have been described and their in vitro cancer growth inhibition activities have been evaluated against three human tumour cell lines (HT-29, M21, and MCF7). In general, growth inhibition activity has been enhanced by the introduction of a bulky substituent on the aromatic ring with the best compound having GI50<6µM for all the human tumour cell lines. The MCF7 selective compounds were evaluated on four additional human invasive breast ductal carcinoma cell lines (MDA-MB-231, MDA-MB-468, SKBR3, and T47D) and were selective against T47D cell line in all cases except one, suggesting a potential antiestrogen activity.

The synthesis of novel sulfamides derived from ß-benzylphenethylamines as acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase enzymes inhibitors.

In this study, a series of novel ß-benzylphenethylamines and their sulfamide derivatives were synthesized starting from (Z)-2,3-diphenylacrylonitriles. Pd-C catalysed hydrogenation of diphenylacrylonitriles, reduction of propanenitriles with LiAlH4 in the presence of AlCl3 followed by addition of conc. HCl afforded ß-benzylphenethylamine hydrochloride salts. The reactions of these amine hydrochloride salts with chlorosulfonyl isocyanate (CSI) in the presence of tert-BuOH and excess Et3N gave sulfamoylcarbamates. Removing of Boc group from the synthesized sulfamoylcarbamates with trifluoroacetic acid (TFA) yielded novel sulfamides in good yields. These novel sulfamides derived from ß-benzylphenethylamines were effective inhibitors of the cytosolic carbonic anhydrase I and II isoenzymes (hCA I and II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with Ki values in the range of 0.278-2.260nM for hCA I, 0.187-1.478nM for hCA II, 0.127-2.452nM for AChE and 0.494-1.790nM for BChE. The inhibitory effects of the synthesized novel sulfamides derived from ß-benzylphenethylamines were compared to those of acetazolamide and dorzolamide as clinical hCA I and II isoenzymes inhibitors and tacrine as a clinical AChE and BChE enzymes inhibitors. In addition to in vitro tests, molecular modeling approaches are implemented not only for prediction of the binding affinities of the compounds but also to study their inhibition mechanisms in atomic level at the catalytic domains.

Sulfamide chemistry applied to the functionalization of self-assembled monolayers on gold surfaces.

Aniline-terminated self-assembled monolayers (SAMs) on gold surfaces have successfully reacted with ArSO2NHOSO2Ar (Ar = 4-MeC6H4 or 4-FC6H4) resulting in monolayers with sulfamide moieties and different end groups. Moreover, the sulfamide groups on the SAMs can be hydrolyzed showing the partial regeneration of the aniline surface. SAMs were characterized by water contact angle (WCA) measurements, Fourier-transform infrared reflection absorption spectroscopy (IRRAS) and X-ray photoelectron spectroscopy (XPS).

From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective.

The endothelin peptides bind to two receptors found on cells of vasculature and in tissues. While the endothelin-A (ETA)-receptor is predominantly expressed in vascular smooth muscle cells, the endothelin-B (ETB)-receptor is also found in endothelial cells, fibroblasts, and neuronal cells. Activation of the endothelin system plays a driving role in several chronic cardiovascular diseases and several endothelin receptor antagonists (ERAs) (bosentan (6), ambrisentan (83) and macitentan (43)) have successfully been introduced as oral treatments for the life threatening condition of pulmonary arterial hypertension (PAH). This digest highlights the medicinal chemistry of the pyrimidine based ERAs 6 and 43 and describes the story that started with bosentan and culminated in macitentan (43). A condensed overview of the competitive landscape in the field of ERAs puts the different strategies and tactics applied by the medicinal chemists involved in this endeavor into perspective.

Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin scaffolds.

In the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC 4.2.1.1) isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2-aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride, followed by conversion to the corresponding phenols via O-demethylation with BBr3. The novel urea and sulfamide derivatives were tested for inhibition of hCA I, II and AChE enzymes. These derivatives exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values of 2.61-3.69nM against hCA I, 1.64-2.80nM against hCA II, and in the range of 0.45-1.74nM against AChE. In silico techniques such as, atomistic molecular dynamics (MD) and molecular docking simulations, were used to understand the scenario of the inhibition mechanism upon approaching of the ligands into the active site of the target enzymes. In light of the experimental and computational results, crucial amino acids playing a role in the stabilization of the enzyme-inhibitor adducts were identified.

Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: novel sulfamoylcarbamates and sulfamides derived from acetophenones.

In this study, several novel sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9±8.9-687.5±84.3 pM for hCA I, and 48.80±8.2-672.2±71.9pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52±0.61-38.28±6.84pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17-21 and sulfamide derivatives 22-26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity.

Acetylcholinesterase inhibitory and antioxidant activities of novel symmetric sulfamides derived from phenethylamines.

The antioxidant and acetylcholinesterase inhibitory properties of novel symmetric sulfamides derived from phenethylamines were evaluated. Phenethylamines 8-11 were reacted with SO2Cl2 in the presence of Et3N to afford sulfamides in good yields. The synthesized sulfamides were converted to their phenolic derivatives with BBr3. We elucidated the antioxidant activity of novel symmetric sulfamides by using different bioanalytical assays. For this purpose, the radical scavenging activities of the novel symmetric sulfamides were assessed by DPPH(•), ABTS(•+), DMPD(•+), and O2(•-) radical scavenging tests. In addition, the reducing abilities of the novel symmetric sulfamides were evaluated by Fe(3+)-Fe(2+) reducing, Cu(2+)-Cu(+) reducing, and [Fe(3+)-(TPTZ)2](3+)-[Fe(2+)-(TPTZ)2](2+) reducing activity tests. Also, the Fe(2+) chelating activity by the pipyrdyl reagent and the acetylcholinesterase inhibitory activities of the novel symmetric sulfamides were studied. Especially, the novel phenolic and symmetric sulfamides 16-19 showed high antioxidant and acetylcholinesterase inhibitory properties. On the other hand, IC50 values were calculated for the DPPH(•), ABTS(•+), DMPD(•+), and O2(•-) scavenging, the metal chelating, and the acetylcholinesterase inhibition effects of the novel symmetric sulfamides.

Anion inhibition studies of two new ß-carbonic anhydrases from the bacterial pathogen Legionella pneumophila.

We investigated the cloning, catalytic activity and anion inhibition of the ß-class carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Legionella pneumophila. Two such enzymes, lpCA1 and lpCA2, were found in the genome of this pathogen. These enzymes were determined to be efficient catalysts for CO2 hydration, with kcat values in the range of (3.4-8.3)×10(5) s(-1) and kcat/KM values of (4.7-8.5)×10(7) M(-1) s(-1). A set of inorganic anions and small molecules was investigated to identify inhibitors of these enzymes. Perchlorate and tetrafluoroborate were not acting as inhibitors (KI >200 mM), whereas sulfate was a very weak inhibitor for both lpCA1 and lpCA2 (KI values of 77.9-96.5 mM). The most potent lpCA1 inhibitors were cyanide, azide, hydrogen sulfide, diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid and phenylarsonic acid, with KI values ranging from 6 to 94 µM. The most potent lpCA2 inhibitors were diethyldithiocarbamate, sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid, with KI values ranging from 2 to 13 µM. As these enzymes seem to be involved in regulation of phagosome pH during Legionella infection, inhibition of these targets may lead to antibacterial agents with a novel mechanism of action.

Carbonic anhydrase inhibitory properties of novel benzylsulfamides using molecular modeling and experimental studies.

In this study, a series of sulfamoyl carbamates and sulfamide derivatives were synthesized. Six commercially available benzyl amines and BnOH were reacted with chlorosulfonyl isocyanate (CSI) to give sulfamoyl carbamates. Pd-C catalyzed hydrogenolysis reactions of carbamates afforded sulfamides. The inhibition effects of novel benzylsulfamides on the carbonic anhydrase I, and II isoenzymes (CA I, and CA II) purified from fresh human blood red cells were determined by Sepharose-4B-L-Tyrosine-sulfanilamide affinity chromatography. In vitro studies were shown that all of novel synthesized benzylsulfamide analogs inhibited, concentration dependently, both hCA isoenzyme activities. The novel benzylsulfamide compounds investigated here exhibited nanomolar inhibition constants against the two isoenzymes. Ki values were in the range of 28.48±0.01-837.09±0.19nM and 112.01±0.01-268.01±0.22nM for hCAI and hCA II isoenzymes, respectively. Molecular modeling approaches were also applied for studied compounds.

Synthesis and carbonic anhydrase inhibitory effects of novel sulfamides derived from 1-aminoindanes and anilines.

Three 1-aminoindanes, four anilines and BnOH or t-BuOH were reacted with chlorosulfonyl isocyanate to give sulfamoyl carbamates. Pd-C catalysed hydrogenolysis reactions of carbamates or deprotection of the Boc group of the carbamates with CF3 CO2 H afforded seven novel sulfamides. Human carbonic anhydrase (hCA) isoenzymes I and II (hCA I and hCA II) were purified from fresh human blood erythrocytes with one-step affinity chromatography on Sepharose 4B-tyrosine-sulfanilamide. The inhibitory properties of the novel sulfamides on both isoenzymes were determined using the esterase activity with 4-nitrophenyl acetate (NPA) as substrate. The tested novel sulfamides derived from 1-aminoindanes and anilines effectively inhibited hCA I and II competitively in the nanomolar range. Among these compounds, the novel sulfamide derivative 17 showed the most potent inhibitory effect against hCA I (Ki : 153.88 nM), while sulfamide derivative 26 showed the highest inhibitory potential against hCA II (Ki : 117.80 nM).

Combining BNCT with carbonic anhydrase inhibition for mesothelioma treatment: Synthesis, in vitro, in vivo studies of ureidosulfamido carboranes.

Mesothelioma is a malignant neoplasm of mesothelial cells caused by exposure to asbestos. The average survival time after diagnosis is usually nine/twelve months. A multi-therapeutic approach is therefore required to treat and prevent recurrence. Boronated derivatives containing a carborane cage, a sulfamido group and an ureido functionality (CA-USF) have been designed, synthesised and tested, in order to couple Boron Neutron Capture Therapy (BNCT) and the inhibition of Carbonic Anhydrases (CAs), which are overexpressed in many tumours. In vitro studies showed greater inhibition than the reference drug acetazolamide (AZ). To increase solubility in aqueous media, CA-USFs were used as inclusion complexes of hydroxypropyl ß-cyclodextrin (HP-ß-CD) in all the inhibition and cell experiments. BNCT experiments carried out on AB22 (murine mesothelioma) cell lines showed a marked inhibition of cell proliferation by CA-USFs, and in one case a complete inhibition of proliferation twenty days after neutron irradiation. Finally, in vivo neutron irradiation experiments on a mouse model of mesothelioma demonstrated the efficiency of combining CA IX inhibition and BNCT treatment. Indeed, a greater reduction in tumour mass was observed in treated mice compared to untreated mice, with a significant higher effect when combined with BNCT. For in vivo experiments CA-USFs were administered as inclusion complexes of higher molecular weight ß-CD polymers thus increasing the selective extravasation into tumour tissue and reducing clearance. In this way, boron uptake was maximised and CA-USFs demonstrated to be in vivo well tolerated at a therapeutic dose. The therapeutic strategy herein described could be expanded to other cancers with increased CA IX activity, such as melanoma, glioma, and breast cancer.

Molecular Study of Pneumocystis jirovecii in Respiratory Samples of HIV Patients in Chile.

Pneumocystis is an opportunistic fungus that causes potentially fatal pneumonia (PCP) in immunocompromised patients. The objective of this study was to determine the prevalence of P. jirovecii in HIV patients through phenotypic and molecular study, to investigate the genetic polymorphisms of P. jirovecii at the mitochondrial gene mtLSU and at the nuclear dihydropteroate synthase gene (DHPS), and by analysis of molecular docking to study the effect of DHPS mutations on the enzymatic affinity for sulfamethoxazole. A PCP prevalence of 28.3% was detected, with mtLSU rRNA genotypes 3 (33.3%) and 2 (26.6%) being the most common. A prevalence of 6.7% (1/15) mutations in the DHPS gene was detected, specifically at codon 55 of the amino acid sequence of dihydropteroate synthase. Molecular docking analysis showed that the combination of mutations at 55 and 98 codons is required to significantly reduce the affinity of the enzyme for sulfamethoxazole. We observed a low rate of mutations in the DHPS gene, and molecular docking analysis showed that at least two mutations in the DHPS gene are required to significantly reduce the affinity of dihydropteroate synthase for sulfamethoxazole.

The sulfamide moiety affords higher inhibitory activity and oral bioavailability to a series of coumarin dual selective RAF/MEK inhibitors.

Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC50=8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED50=4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment.

Expeditious syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990, and its metabolites.

Syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990, that is, N-(benzo[b]thien-3-ylmethyl)-sulfamide and its metabolites are described. [(13)C(15)N]Benzo[b]thiophene-3-carbonitrile was first prepared by coupling of 3-bromo-benzo[b]thiophene with [(13)C(15)N]-copper cyanide. The resultant [(13)C(15)N]benzo[b]thiophene-3-carbonitrile was reduced with lithium aluminum deuteride to give [(13)CD2(15)N]benzo[b]thiophen-3-yl-methylamine; which was then coupled with sulfamide to afford [(13)CD2(15)N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide, the stable isotope-labeled compound with four stable isotope atoms. Direct oxidation of [(13)CD2(15)N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide with hydrogen peroxide and peracetic acid gave the stable isotope-labeled sulfoxide and sulfone metabolites. On the other hand, radioactive (14)C-labeled N-(benzo[b]thien-3-ylmethyl)-sulfamide was prepared conveniently by sequential coupling of 3-bromo-benzo[b]thiophene with [(14)C]-copper cyanide, reduction of the carbonitrile to carboxaldehyde, and reductive amination with sulfamide.