Sulfamide Derivatives Research Articles

Discovery of novel oridonin sulfamide derivatives as potent NLRP3 inhibitors by a visible-light photocatalysis-enabled peripheral editing

The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1β and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, β-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.

In vitro activity of novel 4-iminohydantoin sulfamide derivatives against human cytomegalovirus

In vitro activity of novel 4-iminohydantoin sulfamide derivatives against human cytomegalovirus

Synthesis and Investigation of Antinociceptive, Anti-Inflammatory, and Ulcerogenic Potential of L-Tryptophan and L-Proline Sulfamide Derivatives

Synthesis and Investigation of Antinociceptive, Anti-Inflammatory, and Ulcerogenic Potential of L-Tryptophan and L-Proline Sulfamide Derivatives

Analysis of Biological Activity of Sulfamide Derivatives as Antimicrobial Agents

Sulfamides are significant compounds because of their biological effects on bacteria, fungi, and cancer. The antimicrobial and anticancer properties of sulfamide derivatives have been demonstrated in several microbial strains and cancer cell lines. They have worked mostly in the field of medicinal chemistry. Numerous microbiological pathogens are known to be resistant to the antibacterial effects of sulfamide derivatives. The most significant microorganisms in command of hospital-acquired nosocomial infections include Acinetobacter baumannii (A. baumannii), Methicillin-resistant Staphylococcus aureus (MRSA), Candida albicans (C. albicans), and Candida parapsilosis (C. parapsilosis). Multiple antibiotics can no longer treat these illnesses. Therefore, it is crucial to develop new antimicrobial agents. Three previously made compounds were tested for their antibacterial properties against these pathogens, including 3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,1-dimethyl sulfamide (4) and 3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,1-dimethyl sulfamide (5). Using the disc diffusion method, antimicrobial activity was assessed, and values for the minimum inhibitory concentration (MIC) were calculated for zone formation seen in the tested pathogens. The results of the investigation demonstrated that sulfamide derivatives stopped the growth of bacteria against A. baumannii with zone widths of 7-9 mm, but had no impact on MRSA, C. albicans, and C. parapsilosis. Sulfamide derivatives' MIC values against A. baumannii were discovered to be 3.90 g/ml. These results provide us the ability to evaluate these sulfamide derivatives as potential new antibacterial therapies for A. baumannii.

Determination of radioprotective and genotoxic properties of sulfamide derivatives

Abstract Some potential drug active substances with the ability to reduce the effects of radiation on human tissues and cells were investigated. For this purpose, eight different types of sulfamide derivatives were synthesized and nuclear radiation protection parameters were determined. Neutron radiation reduction parameters such as the half-value layer effective removal cross-sections, mean free path, and the number of particles passing through the sample were determined with GEANT4 code. Additionally, the gamma radiation attenuation parameters of the materials examined were determined using Phy-X/PSD software in the energy area of 0.015–15 MeV. These parameters are the half-value layer, mass attenuation coefficient, mean free path, exposure buildup factor and effective atomic number. Neutron radiation absorption experiments were applied using an 241Am-Be fast neutron source. All results obtained for neutron radiation were compared with paraffin and water. It has been found that the ability of sulfamide derivatives to absorb these radiations is superior to reference materials. To determine whether these derivatives could have adverse effects on human health, their genotoxic potential was determined using the Ames/Salmonella bacterial reversion test. The results showed that these derivatives can be considered genotoxically safe in tests at concentrations up to 5 mM. Thus, it is suggested that the derivative materials examined in this study can be used as active substances for a drug to be made for protection against both neutron and gamma radiation.

New 4-iminohydantoin sulfamide derivatives with antiviral and anticancer activity

A number of sulfamides were obtained by reaction of (5-(dichloromethylene)-2-oxoimidazolidin-4-ylidene)sulfamoyl chloride with anilines, benzylamines, Boc-protected piperazine, methylalylamine, and amino acids methyl esters with primary and secondary amino group. The antiviral and anticancer activity of new derivatives was evaluated. The most effective compounds against Human cytomegalovirus were sulfamides based on anisidine (1b), N-Boc-piperazine (1h), and the derivatives 1n,o with fragments of nipecotic and azetidine-3-carboxylic acids, respectively. Anticancer activity was most significant for sulfamides based on p-methoxybenzylamine (compound 1d), benzylmethylamine (compound 1f), and allylmethylamine (compound 1g).

Toward New Transmission-Blocking Combination Therapies: Pharmacokinetics of 10-Amino-Artemisinins and 11-Aza-Artemisinin and Comparison with Dihydroartemisinin and Artemether.

ABSTRACTAs artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a redox drug, and a third drug with a different mode of action. Thus, here we briefly review efficacy data on artemisone, artemiside, other amino-artemisinins, and 11-aza-artemisinin and conduct absorption, distribution, and metabolism and excretion (ADME) profiling in vitro and pharmacokinetic (PK) profiling in vivo via intravenous (i.v.) and oral (p.o.) administration to mice. The sulfamide derivative has a notably long murine microsomal half-life (t1/2 > 150 min), low intrinsic liver clearance and total plasma clearance rates (CLint 189.4, CLtot 32.2 ml/min/kg), and high relative bioavailability (F = 59%). Kinetics are somewhat similar for 11-aza-artemisinin (t1/2 > 150 min, CLint = 576.9, CLtot = 75.0 ml/min/kg), although bioavailability is lower (F = 14%). In contrast, artemether is rapidly metabolized to dihydroartemisinin (DHA) (t1/2 = 17.4 min) and eliminated (CLint = 855.0, CLtot = 119.7 ml/min/kg) and has low oral bioavailability (F) of 2%. While artemisone displays low t1/2 of <10 min and high CLint of 302.1, it displays a low CLtot of 42.3 ml/min/kg and moderate bioavailability (F) of 32%. Its active metabolite M1 displays a much-improved t1/2 of >150 min and a reduced CLint of 37.4 ml/min/kg. Artemiside has t1/2 of 12.4 min, CLint of 673.9, and CLtot of 129.7 ml/kg/min, likely a reflection of its surprisingly rapid metabolism to artemisone, reported here for the first time. DHA is not formed from any amino-artemisinin. Overall, the efficacy and PK data strongly support the development of selected amino-artemisinins as components of new TACTs.

Synthesis of Novel Pesticidal N,N′-Disubstituted Sulfamide Derivatives Using Sulfur(VI) Fluorine Exchange Click Reaction

Sulfur(VI) fluorine exchange click reaction was applied to the highly efficient synthesis of new N,N'-disubstituted sulfamide (R1NH-SO2-NHR2) derivatives as pesticide candidates. Bioassays were conducted to evaluate both insecticidal and fungicidal activities of the target compounds. Preliminary results showed that the target molecules exhibited good bioactivities. In particular, insecticidal activities of compounds D25 and D21 against Plutella xylostella (LC50 = 2.42 and 3.87 μg·mL-1) were superior or adequate to that of commercial insecticide indoxacarb (LC50 = 3.99 μg·mL-1). Moreover, some compounds could also exhibit satisfactory fungicidal activity toward plant pathogens Pyricularia grisea, Botrytis cinerea, and Thanatephorus cucumeris. This work could bring new insights into the application of heterocyclic N,N'-disubstituted sulfamides as novel pesticides.

Synthesis of nitroxy and nitraza derivatives of 1,1-dinitroalkyldiazene 1-oxides

New high energy nitroxy and nitraza derivatives of 1-(1,1-dinitroalkyl)-2-methyl- and 1-(1,1-dinitroalkyl)-2-furazanyldiazene 1-oxides were synthesized by nitration of the corresponding hydroxy and sulfamide derivatives.

Синтез 3-арилизоксазолов и их сульфамидных производных

Great interest in binuclear aromatic systems containing an isoxazole ring and a sulfamide group is due to the effect of two pharmacophore groups at once on the biological activity of these compounds. This article is devoted to the development of a method for the synthesis of 3-arylisoxazole-containing compounds and their sulfamide derivatives from simple and accessible products of organic synthesis. The target products of the developed multistage schemes are derivatives of various bicyclic systems containing an isoxazole ring and a second aromatic ring associated with a sulfofragment. The synthesis of 3-aryl-5-acylaminoisoxazoles was carried out by sequential conversion of methyl esters of aromatic carboxylic acids into the corresponding nitriles by reaction with acetonitrile in the presence of sodium hydride in dioxane. At the next stage, the nitriles reacted with hydroxylamine in an aqueous solution of sodium hydroxide to form the corresponding bicyclic amines, which were then acylated in acetonitrile with acetic acid chloride in the presence of pyridine. The total yields of 3-aryl-5-N-acylaminoisoxazoles were at least 60%. It was found that the sulfonylchlorination of 3-aryl-5-N-acylamino derivatives of isoxazole, depending on the experimental conditions and the structure of the starting substrates, forms both mono- and disulfochlorides. The regioselectivity of the sulfochlorination reaction of the synthesized bicyclic systems was proved by 1H NMR spectroscopy. The influence of various factors on the course of the sulfochlorination reaction of the synthesized bicyclic systems was studied. The dependence of the direction of the electrophilic attack on the structure of the compounds and on the conditions of the experiment was established. As a result of the performed research, both mono and disulfochlorination products were obtained. With an increase in the reaction time, the disulfonylchlorination product accumulates and the deacylation reaction proceeds in parallel. Convincing proof of the structure of all synthesized compounds has been carried out using a complex of modern methods of physical and chemical analysis.

Optimization of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors for the potential treatment of ischemic brain injury

The 11β-hydroxysteroiddehydrogenase type 1(11β-HSD1), acortisolregenerating enzyme that amplifies tissue glucocorticoidlevels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11β-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC50 value of 1 nM toward human and mouse 11β-HSD1 and showed good 11β-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11β-HSD1 were suggested.

Evaluation of WO2017018805: 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors

ABSTRACTIntroduction: There are great potential in the development of selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine diseases, and other diseases associated with HDAC6 activity.Areas covered: The application claims 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; disease of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities. Many of the exemplified compounds showed nanomole potency against HDAC6 and were more than 5000-fold selectivity for HDAC6 over HDAC1.Expert opinion: These 1,3,4-oxadiazole sulfamide derivatives have a unique zinc-binding group (ZBG) that provide good leads for the discovery of potent selective HDAC6 inhibitors for the treatment of a variety of diseases associated with HDAC6 activity.

Synthesis of novel sulfamides incorporating phenethylamines and determination of their inhibition profiles against some metabolic enzymes.

A series of sulfamides were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carbonic anhydrase inhibition properties. The synthesis of sulfamides was achieved by the reactions of phenethylamines with N,N-dimethylsulfamoyl chloride in the presence of Et3 N. The methoxylated sulfamides were converted into their phenolic derivatives with BBr3 for structure-activity relationships. The synthesized sulfamide/phenolic sulfamide derivatives were investigated as cholinesterase inhibitors and their relative role in AChE versus BChE inhibition was defined. Sulfamide/phenolic sulfamide derivatives are known as important carbonic anhydrase inhibitors; therefore, the synthesized compounds were investigated for inhibitory effects on both carbonic anhydrase isoenzymes. Additionally, we evaluated four different enzymes, which were inhibited in the low nanomolar range by these compounds. According to the present studies, for AChE, BChE, and carbonic anhydrase I and II, the ranges of results are recorded as 0.027-0.076 nM, 0.075-0.327 nM, 0.123-0.678 nM, and 0.024-0.688 nM, respectively.

Synthesis, anti-cancer screening and tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition activity of novel piperidinyl sulfamides

Novel piperidinyl-based sulfamide derivatives were designed and synthesized through various synthetic routes. Anticancer activities of these sulfamides were evaluated by phenotypic screening on National Cancer Institute's 60 human tumor cell lines (NCI-60). Preliminary screening at 10μM concentration showed that piperidinyl sulfamide aminoester 26 (NSC 749204) was sensitive to most of the cell lines in the panel. Further dose-response studies showed that 26 was highly selective for inhibition of colon cancer cell lines with minimum GI50=1.88μM for COLO-205 and maximum GI50=11.1μM for SW-620 cells. These newly synthesized sulfamides were also screening for their Tdp1 inhibition activity. Compound 18 (NSC 750706) showed significant inhibition of Tdp1 with IC50=23.7μM. Molecular-docking studies showed that 18 bind to Tdp1 in its binding pocket similar to a known Tdp1 inhibitor.

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

In this study, a series of novel β-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 β-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 β-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 β-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.

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.

Sulfamide derivatives with selective carbonic anhydrase VII inhibitory action

A set of N,N′-disubstituted sulfamides and sodium cyclamate have been tested for their inhibitory action against six isoforms of carbonic anhydrase (CA, EC 4.2.1.1) found in the brain, that is, CA I, CA II, CA VII, CA IX, CA XII and CA XIV, some of which are involved in epileptogenesis. The biological data showed interesting results for CA VII inhibition, the isozyme thought to be a novel antiepileptic target. Strong CA VII inhibitors, with Ki values in the low nanomolar–subnanomolar range were identified. Some of these derivatives showed selectivity for inhibition of CA VII versus the ubiquitous isoform CA II, for which the Ki values were in the micromolar range. Molecular modeling approaches were employed to understand the binding interactions between these compounds and the two CA isoforms, since the mechanism of action of such disubstituted sulfamides was not yet investigated by means of X-ray crystallography.

Design, synthesis, biological evaluation and molecular docking of amide and sulfamide derivatives as Escherichia coli pyruvate dehydrogenase complex E1 inhibitors

Optimal binding mode of novel E. coli PDHc E1 inhibitor 9d.

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.

Abstract 16349: A Novel Class of Inhibitors That Are Specific to Human NPP1 Prevent Pathologic Mineralization of Valve Interstitial Cells

BACKGROUND: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) is an ectoenzyme, which plays a role into several disorders including calcific aortic valve disease (CAVD). So far, compounds that have been developed as inhibitors of NPP1 lack of potency and specificity. Quinazolin-4-piperidin-4-methyl sulfamide (QPS) derivatives have been described as potent inhibitors of NPP1. However, their mode of inhibition as well as their selectivity and capacity to modify biological processes have not been investigated. METHOD: We have investigated the potency and selectivity of QPS derivatives in inhibiting NPP1 by enzymatic activities. The biological effect of QPS derivatives was documented on the mineralization of valve interstitial cell cultures, apoptosis assay, as well as quantitative polymerase chain reaction. RESULTS: We documented that QPS1 derivative is a potent (67.9 ±5.3 nM) and selective non-competitive inhibitor of human NPP1. Moreover, QPS1 also significantly inhibited the K121Q NPP1 gene variant (ki 51.9±9.8 nM), which is prevalent in the general population. QPS1 did not significantly alter the activity of other nucleotide metabolising enzymes expressed at the cell surface, namely NPP3, NTPDases (1-3), ecto-5’-nucleotidase and ALP. Importantly, QPS1 in the low micromolar range (≤10μM) prevented phosphate-induced mineralization of VICs and lowered the rise of osteogenic genes as expected for NPP1 inhibition. CONCLUSION: We provide evidence that QPS1 is a potent and selective non-competitive inhibitor of NPP1 that prevents pathologic mineralization in a cellular model.