Sulfonamide Moiety Research Articles

Sulfonamide-derivatized galactosides selectively target an unexplored binding site in the galectin-9N-terminal domain

Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-d-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and non-conserved binding site perpendicular to and below the A-B subsite to interact with a His61 NH proton. This resulted in the discovery of galectin-9N inhibitors with unprecedented selectivity over other galectins, thus constituting valuable tools for studies of the biological functions of galectin-9.

Synthesis of New Tetracyclic Ring Systems: Bridged Derivatives of Hydroxy‐, Sulfanyl‐ and Amino‐Substituted Dibenzo[c,f][1,2]Thiazepine S,S‐Dioxides

AbstractIn continuation of our commitment to the synthesis of new ring systems based on the 6,11‐dihydrodibenzo[c,f][1,2]thiazepine 5,5‐dioxide core of the antidepressant drug tianeptine, we have incorporated two‐ and/or three‐carbon bridges between the nitrogen atom of the sulfonamide moiety and the N‐, O‐ or S‐substituent at position 11 of the tricycle. The synthesis of 5 new ring systems is described and demonstrated with several target compounds.

Lactoperoxidase Inhibition of Celecoxib Derivatives Containing the Pyrazole Linked-Sulfonamide Moiety: Antioxidant Capacity, Antimicrobial Activity, and Molecular Docking Studies.

Celecoxib derivatives that contain the pyrazole-linked sulfonamide moiety were synthesized, and the in vitro inhibitory impacts of the aforesaid compounds against the lactoperoxidase (LPO) enzyme were researched. To this end, LPO was purified using the affinity chromatography technique with a yield of 12.63% (319.23-fold). The results showed that the aromatic pyrazole compound (compound 1) containing 2,3-dimethoxyphenyl functional groups was the most effective LPO inhibitor with a Ki value of 3.2 ± 0.7 nM and noncompetitive inhibition type. The second section of the study tested the previously synthesized compounds to reveal their antioxidant and antimicrobial properties. The above-mentioned compound also displayed high activity levels compared to standard antibiotics and antifungals, while all other compounds also showed antibacterial activity. In the three antioxidant methods we used, the compound with 2,5-dimethoxy phenyl groups obtained from the reaction of the aromatic pyrazole compound with propionic anhydride in the presence of NEt3 displayed the highest activity. Furthermore, molecular docking and molecular mechanics studies were conducted to complement and validate the experimental findings. The results obtained from these computational analyses are highly consistent with the experimental data.

Design, Synthesis, Biological Evaluation and Molecular Docking Studies of New Thiazolidinone Derivatives as NNRTIs and SARS-CoV-2 Main Protease Inhibitors.

HIV-1 remains a major health problem worldwide since the virus has developed drug-resistant strains, so, the need for novel agents is urgent. The protein reverse transcriptase plays fundamental role in the viruses' replication cycle. FDA approved Delavirdine bearing a sulfonamide moiety, while thiazolidinone has demonstrated significant anti-HIV activity as a core heterocycle or derivative of substituted heterocycles. In this study, thirty new thiazolidinone derivatives (series A, B and C) bearing sulfonamide group were designed, synthesized and evaluated for their HIV-1 RT inhibition activity predicted by computer program PASS taking into account the best features of available NNRTIs as well as against SARS-COV-2 main protease. Seven compounds showed good anti-HIV inhibitory activity, with two of them, C1 and C2 being better (IC50 0.18 μΜ & 0.12 μΜ respectively) than the reference drug nevirapine (IC50 0.31 μΜ). The evaluation of molecules to inhibit the main protease revealed that 6 of the synthesized compounds exhibited excellent to moderate activity with two of them (B4 and B10) having better IC50 values (0.15 & 0.19 μΜ respectively) than the reference inhibitor GC376 (IC50 0.439 μΜ). The docking studies is coincides with experimental results, showing good binding mode to both enzymes.

Synthesis and investigation of selective human carbonic anhydrase IX, XII inhibitors using coumarins bearing a sulfonamide or biotin moiety

The role of carbonic anhydrases isoforms (CAs) IX and XII in the pathogenesis and progression of many types of solid tumors is well known. In this context, selective CA inhibitors (CAIs) towards the mentioned isoforms is a validated strategy for the development of agents to target cancer. For this purpose, novel coumarin derivatives based on the hybridization with arylsulfonamide or biotin scaffolds were synthesized and tested as inhibitors of four different human carbonic anhydrases isoforms: hCA I, II, IX and XII. Coumarin-sulfonamide derived 27, with a thiourea moiety and triazole as linker, showed the highest inhibition activity against hCA XII with an inhibition constant (KI) of 7.5 nM and afforded a very good selectivity over hCA I. Compound 32 was the most potent inhibitor against hCA IX (KI = 6.3 nM), 4-fold stronger than the drug acetazolamide AAZ (KI = 25 nM), used herein as a reference compound, and showed remarkable selectivity over hCA I and II. The coumarin-biotin derivatives 37–39 showed outstanding selectivity towards on-target enzymes (hCA IX and XII) and appear as plausible leads for designing of CAIs.

Preyssler heteropolyacid-mediated direct deprotection/N-benzoylation of N-Boc-protected sulfonamides: synthesis, molecular docking, DFT study and in-silico ADME evaluation of novel benzamides bearing the sulfonamide moiety as possible inhibitors of human carbonic anhydrase II

An adequate method is described for the synthesis of new substituted benzamides containing a sulfonamide moiety using Preyssler heteropolyacid H14[NaP5W30O110] as an efficient catalyst. This method proceeds in one-step, including deprotection and benzoylation of N-(tert-butoxycarbonyl) sulfonamides to give the target compounds good yields (up to 92%). A molecular docking was performed to study the interactions between the synthesized benzamides and human carbonic anhydrases II. It was concluded that all compounds demonstrated good binding score values (up to −9.4 kcal/mol) for the active site of all selected proteins when compared with the reference drug Acetazolamide (−6.3 kcal/mol). In addition, the ADME/T analyses show that all synthesized molecules exhibited good pharmacokinetics and bioavailability. The theoretical calculations for all compounds were performed using the DFT/B3LYP/6–31G (d,p) level of theory. The study yielded optimized structural parameters, global reactivity descriptors, and Frontier Molecular Orbitals (FMO’s).

Development of Novel 1,3,4‐Trisubstituted Pyrazole Derivatives Bearing Sulfonamide Moiety as Anticancer Agents Targeting JNK Kinases

AbstractIn the present work, a new set of N‐(2‐((4‐(1,3‐diphenyl‐1H‐pyrazol‐4‐yl)pyridine sulfonamide derivatives was synthesized. Final target compounds were tested against JNK1 and JNK2 isoforms. Compounds 8f and 8d showed the highest activity over both JNK isoforms. They showed submicromolar activity over JNK1 (IC50 0.90 µM and 0.96 µM, respectively). They also showed excellent activity over JNK2 (IC50 0.62 µM and 1.07 µM, respectively). Moreover, the final target compounds were tested over HL‐60 and K‐562 cell lines for assessing the in vitro anticancer activity using sorafenib as a positive control. Compound 8f showed the highest potency at IC50 values of 6.21 and 7.43 µM, respectively. Furthermore, compounds 8e and 8g exhibited strong effects on both acute leukemia cancer cell lines with IC50 values of 13.83 and 10.02 µM, respectively, as well as chronic leukemia cancer cell line with IC50 of 12.65 and 9.51 µM, respectively. Compound 8f was also tested to examine its effect on the cell cycle. Finally, a molecular docking study was conducted to understand the plausible binding modes of the most active compounds 8d and 8f within the JNK1 and JNK2 binding sites.

Sulfonamides and sulfonate esters: Synthetic routes, proposed mechanisms, and crystallographic characterizations

The sulfonamide and sulfonate moieties are key structural features in many pharmaceuticals, agrochemicals, and materials and have proven useful as synthetic precursors. In this review, synthetic routes for sulfonamides and sulfonate esters were examined to gain insight into the mechanism behind the sulfonylation of amines and alcohols, which remains largely unknown and highly dependent on the reaction conditions used. Furthermore, the review delves into crystallographic characterizations of previously reported sulfonamide and sulfonate ester compounds, unraveling trends associated with crucial steric and electronic factors that influence their crystallization. This exploration not only enhances our understanding of the structural nuances of these compounds, but also paves the way for informed design strategies in synthetic and medicinal chemistry. In essence, this review endeavors to provide a holistic perspective on sulfonamides and sulfonate esters, bridging the realms of synthesis, mechanism elucidation, and structural characterization.

Anticancer and anti-inflammatory effects of novel ethyl pyrazole derivatives having sulfonamide terminal moiety

In the present work, a new series of ethyl pyrazole-containing compounds with side sulphonamide moiety was designed and synthesized. The new derivatives were divided into four groups based on the linker between the sulphonamide and pyridine ring attached to position 4 of the pyrazole ring and the substitution on the phenyl ring at position 3 of the same ring. The linker could be ethyl or propyl linkers. The phenyl ring is substituted with a methoxy group or hydroxyl group at position 3. The aim compounds were tested for their JNK1, JNK2, JNK3, and BRAF(V600E) activities. Compounds 23b, 23c, and 23d showed the highest activity with nanomolar IC50s. The most potent compound over JNK1 was 23d with an IC502 nM. While compound 23c was the most potent over JNK2 with an IC5057 nM. Finally, compound 23b was the most potent over JNK2 and BRAF(V600E) with IC50s of125 nM and 98 nM, respectively. After obtaining kinase inhibitory activity, the compounds were submitted to NCI to test their activity over different cell lines. Compound 23b showed the highest activity over most tested cell lines. In the second part of the present study, the final target compounds were tested for their anti-inflammatory effect. The anti-inflammatory effect of the new final compounds was performed by measuring their ability to inhibit inducible nitric oxide release and prostaglandin E2 production inhibition. Compound 23c showed the highest activity regarding nitric oxide release with IC50 0.63 μM, while compound 21d had the highest activity regarding prostaglandin E2 production with IC50 0.52 μM. The effect of the most potent compounds was tested by western blot against iNOS, COX-1, and COX-2.

Synthesis and Biological Evaluation of Novel Coumarin Derivatives Bearing a Sulfonamide Moiety as Antiviral and Antibacterial Agent

AbstractTwenty novel 4-bromocoumarin derivatives bearing a sulfonamide moiety were designed and synthesized. Their antiviral and antibacterial activities were systematically evaluated. The test results show that all the target compounds possess moderate to excellent antiviral and antibacterial activities. Among all target compounds, one compound exhibited good antiviral activity against TMV, CMV, and PVY, which is superior to ribavirin. Moreover, two target compounds exhibited good in vitro antibacterial activity against Psa, with an EC50 value of 44.9 mg/L and 49.3 mg/L, respectively, which were better than thiodiazole copper and zinc thiazole, with an EC50 value of 56.3 mg/L and 50.2 mg/L, respectively. The results provide insights for the development of multifunctional pesticides.

Synthesis, molecular docking and molecular dynamics simulations, drug-likeness studies, ADMET prediction and biological evaluation of novel pyrazole-carboxamides bearing sulfonamide moiety as potent carbonic anhydrase inhibitors.

Pyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds containing sulfonamide nuclei also attract attention as carbonic anhydrase (CA) inhibitors. In this study, a library of pyrazole-carboxamides were synthesized and the structures of the synthesized molecules were characterized using FT-IR, 1H-NMR, 13C-NMR and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.063-3.368µM for hCA I and 0.007-4.235µM for hCA II. Molecular docking studies were performed between the most active compounds 6a, 6b and the reference inhibitor, acetazolamide (AAZ) and the hCA I and hCA II receptors to investigate the binding mechanisms between the compounds and the receptors. These compounds showed better interactions than the AAZ. ADMET analyzes were performed for the compounds and it was seen that the compounds did not show AMES toxicity. The stability of the molecular docking results over time was analysed by 50ns molecular dynamics simulations. Molecular dynamics simulations revealed that 6a and 6b exhibited good stability after docking to the binding sites of hCA I and hCA II receptors, with minor conformational changes and fluctuations.

Discovery of novel piperidine-containing thymol derivatives as potent antifungal agents for crop protection.

Plant fungal diseases pose a significant threat to crop production. The extensive use of chemical pesticides has led to growing environmental safety risks and pesticide resistance of various plant pathogens. Therefore, it is an urgent task to explore novel eco-friendly fungicidal agents with high efficacy to combat fungal infection. In this study, we rationally designed a series of novel thymol derivatives by incorporation of the sulfonamide moiety and evaluated their biological activities against plant pathogenic fungi. The bioassay results underscored the remarkable in vitro antifungal activity of compounds 5m and 5t against Phytophthora capsici (P. capsici), with EC50 values of 8.420 and 8.414 μg/mL, respectively. Their efficacies were superior to that of widely used commercial fungicides azoxystrobin (AZO, 20.649 μg/mL) and cabendazim (CAB, 251.625 μg/mL). Furthermore, compound 5v exhibited excellent in vitro antifungal activity against Sclerotinia sclerotiorum (S. sclerotiorum), with an EC50 value of 12.829 μg/mL, significantly outperforming AZO (63.629 μg/mL). In vivo bioassays demonstrated the impactful activity of compound 5v against S. sclerotiorum, achieving over 98% curative and protective efficacies at the concentration of 200 μg/mL. Further mechanistic investigations unveiled that compound 5v induced mycelial shrinkage and collapse in S. sclerotiorum, resulting in organelle damage and the accumulation of antioxidant enzyme activity. The significant antifungal efficacy of the prepared thymol derivatives shall encourage further exploration of compound 5v as a promising candidate to develop novel fungicides for crop protection. © 2024 Society of Chemical Industry.

Synthesis, structure of the N-(Alkyl/Arylsulfonyl) substituted 5-(Bromo/Iodo)-3-methylindazoles and bioactivity screening against some of the biochemical targets linked to type 2 diabetes mellitus

The indazole scaffold and sulfonamide moiety have evoked high interest in medicinal chemistry especially in the context of antidiabetic drug development. A series of the C-5 unsubstituted (2a–f), 5‑bromo (2g–l) and 5-iodo (2m–r) substituted 1-(alkyl/arylsulfonyl)-3-methylindazoles were prepared, characterized and then evaluated through enzymatic assay in vitro for anti-α-glucosidase activity and for potential free radical scavenging properties. Compounds 2b, 2d, 2f–h, 2k, 2p and 2q exhibited strong activity against α-glucosidase compared to acarbose (IC50 = 1.30 ± 0.02 µM) with IC50 values in the range of 0.72 ± 0.03 – 1.20 ± 0.01 µM. These compounds exhibited increased or strong 2,2-diphenyl-1-picrylhydrazyl (DPPH) and/or nitric oxide (NO) free radical scavenging activities. The compounds were, in turn, evaluated through enzymatic assays in vitro for the potential to inhibit or activate superoxide dismutase (SOD), lipoxygenase-15 (LOX-15) and/or vascular endothelial growth factor receptor-2 (VEGFR-2) activities. An in vitro cell-based antioxidant activity assay involving lipopolysaccharide induced reactive oxygen species (ROS) production in the human breast (MCF-7) cancer cell line revealed that compounds 2d, 2f and 2h exhibit moderate activity (35.5 %, 47 % and 28 %, respectively) compared to staurosporine (24 %). Compounds 2d, 2f and 2h significantly reduced the ROS level in the human embryonic kidney (HEK293-T) cells (65.5 %, 58 % and 48 %, respectively) compared to staurosporine (34 %). The planar benzo-fused heterocyclic scaffold and the distorted tetrahedral geometry of the N-sulfonyl moiety are predicted to facilitate hydrophobic and/or hydrogen bonding interactions to stabilize protein-ligand interaction in the receptors. The ADME analysis predicted that the test compounds have drug-like properties, a safe toxicity profile in silico without any carcinogenic and mutagenicity side effect. Molecular modelling was also used to attempt to rationalize the biological activity of these compounds and to correlate the results of in vitro and in silico studies.

In(OTf)3 promoted sonochemical approach to 3-(2-chloropyrimidin-4-yl)indoles: Their in silico and in vitro evaluation against SIRT1

We report exploring the 3-(2-chloropyrimidin-4-yl)indole framework for the identification of new inhibitors of SIRT1. A library of compounds based on this framework was synthesized via an ultrasound assisted heteroarylation approach. The methodology involved In(OTf)3 mediated CC bond forming reaction between 2,4-dichloropyrimidine and indoles to give the desired products in good to acceptable yields. The regioselectivity of this approach appeared to be a key feature as the methodology involved sonochemical replacement of the (i) C-3 hydrogen of indole and (ii) C-4 chloro group of the pyrimidine ring at the same time. Its synthetic application was demonstrated by converting one of the synthesized compounds into the naturally occurring alkaloid Meridianin G. The in silico docking of 3-(2-chloropyrimidin-4-yl)indoles prepared showed promising interactions with SIRT1 in addition to probable selectivity towards this protein over SIRT2. A majority of compounds participated in H-bond interaction with GLN345 residue mainly through their indole “NH” moiety. However, higher binding affinities were observed for compounds possessing a sulfonamide moiety at C-5 position of the indole ring. Correlating the findings of in silico studies a number of synthesized compounds showed inhibition of SIRT1 in vitro. With the inhibition > 70 % the compound 3e, 3o and 3p were identified as initial hit molecules when 3p emerged as most promising among them. The SAR (Structure-Activity-Relationship) analysis also suggested that a sulfonamide moiety at C-5 position was beneficial for the high SIRT1 inhibition whereas a free NH moiety of the indole ring was essential for activity. Based on in silico and in vitro studies including ADME predictions the compound 3p appeared as a key agent for further pharmacological evaluation.

Acyl pyrazole sulfonamides as new antidiabetic agents: synthesis, glucosidase inhibition studies, and molecular docking analysis.

Diabetes mellitus is a multi-systematic chronic metabolic disorder and life-threatening disease resulting from impaired glucose homeostasis. The inhibition of glucosidase, particularly α-glucosidase, could serve as an effective methodology in treating diabetes. Attributed to the catalytic function of glucosidase, the present research focuses on the synthesis of sulfonamide-based acyl pyrazoles (5a-k) followed by their in vitro and in silico screening against α-glucosidase. The envisaged structures of prepared compounds were confirmed through NMR and FTIR spectroscopy and mass spectrometry. All compounds were found to be more potent against α-glucosidase than the standard drug, acarbose (IC50 = 35.1 ± 0.14µM), with IC50 values ranging from 1.13 to 28.27µM. However, compound 5a displayed the highest anti-diabetic activity (IC50 = 1.13 ± 0.06µM). Furthermore, in silico studies revealed the intermolecular interactions of most potent compounds (5a and 5b), with active site residues reflecting the importance of pyrazole and sulfonamide moieties. This interaction pattern clearly manifests various structure-activity relationships, while the docking results correspond to the IC50 values of tested compounds. Hence, recent investigation reveals the medicinal significance of sulfonamide-clubbed pyrazole derivatives as prospective therapeutic candidates for treating type 2 diabetes mellitus (T2DM).

Design, Synthesis, and Antimicrobial Evaluation of Novel Sulfonamide Modified with Azoles

Abstract: Sulfonamide, imidazole, and triazole chemical nuclei possess good antimicrobial potential. This study aimed to amalgamate sulfonamide, imidazole, and triazole moieties in a single molecular framework with the intent of improving their antimicrobial activities. The objective of this study was the synthesis of conjugates containing sulfonamide and azole moieties along with in vitro and in silico evaluation as antimicrobial candidates. A series of sulfonamide-modified azoles (7a-r) was synthesized by multicomponent condensation of 1,2-dicarbonyl compounds, ammonium acetate and aryl-substituted aldehydes in glacial acetic acid. The structure of synthesized molecules was elucidated with the help of various spectroscopic techniques, such as FTIR, NMR, and HRMS. The target molecules were tested for in vitro antimicrobial potency against four bacterial strains and two fungal strains. Molecules 7c (MIC 0.0188 μmol/mL), 7f (MIC 0.0170 μmol/mL) and 7i (MIC 0.0181 μmol/mL) were most active against S. aureus and C. albicans. Against E. coli, molecules 7d (MIC 0.0179 μmol/mL), 7f (MIC 0.0170 μmol/mL) and 7i (MIC 0.0181 μmol/mL) were found to be highly active. Moreover, the binding conformations were investigated by insilico molecular docking, and QTAIM (Quantitative theory of atoms in the molecule) analysis was also performed. Molecular properties, such as the heat of formation, HOMO energy, LUMO energy and COSMO volume, were found to be in direct correlation with the antimicrobial potency of molecules 7c, 7f and 7i against S. aureus and C. albicans. All the synthesized molecules were more potent than clinically approved sulfonamides, namely sulfadiazine and sulfabenzamide.

Synthesis, molecular docking analysis, drug-likeness evaluation, and inhibition potency of new pyrazole-3,4-dicarboxamides incorporating sulfonamide moiety as carbonic anhydrase inhibitors.

A series of novel pyrazole-dicarboxamides were synthesized from pyrazole-3,4-dicarboxylic acid chloride and various primary and secondary sulfonamides. The structures of the new compounds were confirmed by FT-IR, 1H-NMR, 13C-NMR, and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.024-0.496 µM for hCA I and 0.006-5.441 µM for hCA II. Compounds 7a and 7i showed nanomolar level of inhibition of hCA II, and these compounds exhibited high selectivity for this isoenzyme. Molecular docking studies were performed between the most active compounds 7a, 7b, 7i, and the reference inhibitor AAZ and the hCAI and hCAII to investigate the binding mechanisms between the compounds and the isozymes. These compounds showed better interactions than the AAZ. ADMET and drug-likeness analyses for the compounds have shown that the compounds can be used pharmacologically in living organisms.

Triazole-bearing sulfonamide linkage: Synthesis, characterization, and investigation as a versatile corrosion inhibitor

Novel focused three 1,4-disubstituted-1,2,3-triazoles 5a-c labeled ISMs (ISM-H, ISM-F & ISM-N) and tethering sulfonamide moieties were designed and synthesized by the 1,3-dipolar cycloaddition of some appropriate aromatic O-alkyne derivatives 3a-c and 4-azido-N-carbamimidoylbenzenesulfonamide 4 as an efficient and common approach in click chemistry. The structures of the resulted click products were elucidated based on their spectral data. The newer synthesized triazoles were well investigated as corrosion inhibitors for carbon steel and Al alloy in HCl solution utilizing electrochemical, weight loss, surface research, and density functional theory (DFT) techniques. The electrochemical impedance spectroscopy (EIS) results revealed that a low inhibitor dosage of compounds ISM-H and ISM-F exhibited potential corrosion inhibition. The ISM-N and ISM-H derivatives exhibited a chemisorption nature and showed the potential inhibition at 60 °C. The surface studies: scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX) and Fourier Transform Infrared Spectroscopy (FTIR) reveals the formation inhibitor film above the metal surface.

The dopamine D2 receptors antagonist Veralipride inhibits carbonic anhydrases: solution and crystallographic insights on human isoforms.

The inhibitory effects of veralipride, a benzamide-class antipsychotic acting as dopamine D2 receptors antagonist incorporates a primary sulfonamide moiety and was investigated for its interactions with carbonic anhydrase (CA) isoforms. In vitro profiling using the stopped-flow technique revealed that veralipride exhibited potent inhibitory activity across all tested hCA isoforms, with exception of hCA III. Comparative analysis with standard inhibitors, acetazolamide (AAZ), and sulpiride, provided insights for understanding the relative efficacy of veralipride as CA inhibitor. The study reports the X-ray crystal structure analysis of the veralipride adduct with three human (h) isoforms, hCA I, II, and CA XII mimic, allowing the understanding of the molecular interactions rationalizing its inhibitory effects against each isoform. These findings contribute to our understanding of veralipride pharmacological properties and for the design of structural analogs endowed with polypharmacological properties.

Design, Synthesis, and Bioevaluation of Novel Reversibly Photoswitchable PI3K Inhibitors Based on Phenylazopyridine Derivatives toward Light-Controlled Cancer Treatment.

Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans- and cis-configuration under irradiation with proper wavelengths. Molecular docking studies show the cis-isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS365 (cis-isomer enriched) was more potent than that in the PSSdark (trans-isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis-isomer, the trans-isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.