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Recently we described a novel class of imidazopyridine compounds that showed exceptional anti-RSV potency in cell culture. However, unfavorable pharmacokinetic (PK) properties and glutathione (GSH) adduct liabilities impeded their further development. In a bid to address the PK and early safety concerns, a small compound library consisting of dozens of scaffold-hopping analogues was designed and synthesized for RSV CPE assay screening, which led to the identification of a new chemical starting point: methylsulfonyl indole compound 8 . In this paper, we report the discovery and optimization of a series of methylsulfonyl indazoles as potent RSV fusion inhibitors. In particular, compound 47 was orally efficacious in a RSV mouse model, with 1.6 log unit viral load reduction at 25 mg/kg BID upon oral dosing. The results may have broad implications for the design of new RSV fusion inhibitors, and demonstrate the potential for developing novel therapies for RSV infection. [ABSTRACT FROM AUTHOR]

Viral infectivity factor (Vif) is protective against APOBEC3G (A3G)-mediated viral cDNA hypermutations, and development of molecules that inhibit Vif mediated A3G degradation is a novel strategy for blocking HIV-1 replication. Through optimizations of the central ring of N -(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide ( RN-18 ), we found a potent compound 12c with EC 50 value of 1.54 μM, enhancing the antiviral activity more than 150-fold compared with RN-18 in nonpermissive H9 cells. 12c protected A3G from degradation by inhibiting Vif function. Besides, 12c suppressed different HIV-1 clinical strains (HIV-1 KM018 , HIV-1 TC-1 and HIV-1 WAN ) and drug-resistant strains (NRTI, NNRTI, PI, and FI) with relatively high activities. Amidation of 12c with glycine gave a prodrug 13a , improving the water solubility about 2600-fold compared with 12c . Moreover, 13a inhibited the virus replication efficiently with an EC 50 value of 0.228 μM. These results suggested that the prodrug 13a is a promising candidate agent for the treatment of AIDS. [ABSTRACT FROM AUTHOR]

A series of 3-arylsulfonylspiroimidazolidine-2,4-diones ( 2a-g ) and their corresponding rearranged products, 1-arylsulfonylspiroimidazolidine-2,4-diones ( 3a-g ) were synthesized and evaluated for antidiabetic and aldose reductase inhibition activity. Three of the compounds ( 2b , 2c and 3c ) were found more potent in-vivo hypoglycemic agents than the commercial drug glibenclamide. The free energy of binding (ΔG) values showed that the compounds are active against aldose reductase and aldehyde reductase enzymes, which was also estimated using molecular mechanics Poisson-Boltzmann surface area method. Of the tested compounds, 2b was found to be the most potent in-vitro selective inhibitor of ALR2 possessing an IC 50 value of 0.89 μ m . Structure activity relationship and molecular docking revealed the importance of substitution features of aryl group of aryllsulfonylimidazolidine-2,4-dione scaffold. It was observed that the substitution with a halogen at para position of the aryl group had a remarkable effect on ALR2 inhibition potency. [ABSTRACT FROM AUTHOR]

The reaction of arylsulfones 11a–d with hydrazonoyl chloride derivative 13 furnished celecoxib analogs 4-(3-acetyl-5-aryl-4-(arylsulfonyl)-1H-pyrazol-1-yl)benzenesulfonamides 15a–d, respectively. Oximes 16a, b and hydrazones 17a, b were prepared by reacting sulfones 11a, b with hydroxyl amine and phenyl hydrazine, respectively. The anti-inflammatory activity of the synthesized compounds showed that, 5-(4-bromophenyl)-4-(phenylsulfonyl)pyrazole 15c and 5-(4-bromophenyl)-4-(4-tolylsulfonyl)pyrazole 15d exhibited excellent anti-inflammatory activity with ED50 = 68 ± 2.2 and 51 ± 0.7 μM/kg, respectively, higher than that of celecoxib (ED50 = 86 ± 1.1 μM/kg) after 3 h with acceptable ulcer index. In addition, the LD50 of 15c and 15d is 7.1 mM/kg for each, and 9.8 mM/kg for celecoxib. Compound 15d appeared selectivity index (COX-2/COX-1) almost the half of celecoxib while 15c is non-selective for COX-2. Compound 15c with ED50 = 80 ± 2.8 μM/kg showed a significant analgesic activity when compared with celecoxib (ED50 = 70 ± 3.9 μM/kg) after 2 h whereas 15b (ED50 = 50 ± 1.2 μM/kg) and 15d (ED50 = 69 ± 2.7 μM/kg) seemed to be more potent than celecoxib (ED50 = 156 ± 4.8 μM/kg) but with a shorter duration (0.5 h). [ABSTRACT FROM AUTHOR]

The present study described the synthesis of original R/S-6-alkylsulfonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyrans bearing a 3- or 4-substituted phenylthiourea or phenylurea moiety at the 4-position. Their biological effects were evaluated both on insulin-secreting and smooth muscle cells and were compared to those of reference KATP channel activators such as (±)-cromakalim, diazoxide and previously synthesized cromakalim analogues. The study aimed at exploring the influence of the introduction of an alkylsulfonylamino substituent at the 6-position of 2,2-dimethylchromans in order to improve biological activity, tissue selectivity but also hydrophilicity of dihydrobenzopyran derivatives. Several compounds were found to be equipotent or even more potent than (±)-cromakalim and diazoxide at inhibiting the insulin releasing process. Most of the newly synthesized and more hydrophilic dihydrobenzopyrans also exhibited a marked vasorelaxant activity although they were less potent than (±)-cromakalim. Additional pharmacological and radioisotopic investigations suggested that R/S-N-3-chlorophenyl-Nʹ-(3,4-dihydro-6-methylsulfonylamino-2,2-dimethyl-2H-1-benzopyran-4-yl)thiourea (21) did not act as a potassium channel opener but rather as a Ca2+ entry blocker. [ABSTRACT FROM AUTHOR]

Abstract: Novel macrocyclic molecules comprising sulfonyl and acyl moiety at the position N-12a of 16-membered azalides (6a–n) and azalactams (10a–r) scaffold were synthesized from cyclododecanone 1 as starting material via 5 steps and 4 steps, respectively. The antifungal activity of these compounds against Sclerotinia sclerotiorum, Pyricularia oryzae, Botrytis cinerea, Rhizoctonia solani and Phytophthora capsici were evaluated and found that compounds possessing α-exomethylene (6c, 6d, 6e and 6g) showed antifungal activity comparable to commercial fungicide Chlorothalonil against P. oryzae and compounds possessing p-chlorobenzoyl exhibited enhanced antifungal activity than those with other substituents against S. sclerotiorum, P. oryzae, and B. cinerea. These findings suggested that the α-exomethylene and p-chlorobenzoyl may be two potential pharmacological active groups with antifungal activities. [Copyright &y& Elsevier]

The emergence of the C797S mutation in EGFR is a frequent mechanism of resistance to osimertinib in the treatment of non-small cell lung cancer (NSCLC). In the present work, we report the design, synthesis and biochemical characterization of UPR1444 (compound 11), a new sulfonyl fluoride derivative which potently and irreversibly inhibits EGFRL858R/T790M/C797S through the formation of a sulfonamide bond with the catalytic residue Lys745. Enzymatic assays show that compound 11 displayed an inhibitory activity on EGFRWT comparable to that of osimertinib, and it resulted more selective than the sulfonyl fluoride probe XO44, recently reported to inhibit a significant part of the kinome. Neither compound 11 nor XO44 inhibited EGFRdel19/T790M/C797S triple mutant. When tested in Ba/F3 cells expressing EGFRL858R/T790M/C797S, compound 11 resulted significantly more potent than osimertinib at inhibiting both EGFR autophosphorylation and proliferation, even if the inhibition of EGFR autophosphorylation by compound 11 in Ba/F3 cells was not long lasting. [Display omitted] • 2-anilinopyrimidines bearing warheads targeting Lys745 were synthetized. • Sulfonyl fluoride 11 (UPR1444) irreversibly inhibits EGFRL858R/T790M/C797S. • HRMS confirms Lys745 sulfonylation by UPR1444. • UPR1444 inhibits proliferation of Ba/F3 cells expressing EGFRL858R/T790M/C797S. [ABSTRACT FROM AUTHOR]

Abstract: Two groups of coumarin–pyrazoline hybrids were synthesized. The target compounds were obtained by cyclization of the coumarin chalcones with various substituted hydrazines to produce the corresponding pyrazolines through 1,4-addition on α,β-unsaturated carbonyl system. Selected compounds were investigated for their anticancer activity toward 60 cancer cell lines according to US NCI protocol where breast cancer MCF7 and colon cancer HCT-116 were the most susceptible to the influence of compounds 7d, 8c and 9c. Encouraged by this, all final compounds were screened against colorectal cell line HCT-116. The tested compounds exhibited high potency with IC50 ranging from 0.01 μM to 2.8 μM. Moreover, compound 9c which possessed the highest cytotoxicity proved to have weak enzyme inhibitory activity against PI3K (p110α/p85α). [Copyright &y& Elsevier]

Alzheimer's disease (AD) is multifactorial, progressive neurodegeneration with impaired behavioural and cognitive functions. The multitarget-directed ligand (MTDL) strategies are promising paradigm in drug development, potentially leading to new possible therapy options for complex AD. Herein, a series of novel MTDLs phenylsulfonyl-pyrimidine carboxylate (BS-1 to BS-24) derivatives were designed and synthesized for AD treatment. All the synthesized compounds were validated by 1HNMR, 13CNMR, HRMS, and BS-19 were structurally validated by X-Ray single diffraction analysis. To evaluate the plausible binding affinity of designed compounds, molecular docking study was performed, and the result revealed their significant interaction with active sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The synthesized compounds displayed moderate to excellent in vitro enzyme inhibitory activity against AChE and BuChE at nanomolar (nM) concentration. Among 24 compounds (BS-1 to BS-24), the optimal compounds (BS-10 and BS-22) displayed potential inhibition against AChE; IC 50 = 47.33 ± 0.02 nM and 51.36 ± 0.04 nM and moderate inhibition against BuChE; IC 50 = 159.43 ± 0.72 nM and 153.3 ± 0.74 nM respectively. In the enzyme kinetics study, the compound BS-10 displayed non-competitive inhibition of AChE with Ki = 8 nM. Respective compounds BS-10 and BS-22 inhibited AChE-induced Aβ 1-42 aggregation in thioflavin T-assay at 10 μM and 20 μM, but BS-10 at 10 μM and 20 μM concentrations are found more potent than BS-22. In addition, the aggregation properties were determined by the dynamic light scattering (DLS) and was found that BS-10 and BS-22 could significantly inhibit self-induced as well as AChE-induced Aβ 1-42 aggregation. The effect of compounds (BS-10 and BS-22) on the viability of MC65 neuroblastoma cells and their capability to cross the blood-brain barrier (BBB) in PAMPA-BBB were further studied. Further, in silico approach was applied to analyze physicochemical and pharmacokinetics properties of the designed compounds via the SwissADME and PreADMET server. Hence, the novel phenylsulfonyl-pyrimidine carboxylate derivatives can act as promising leads in the development of AChE inhibitors and Aβ disaggregator for the treatment of AD. [Display omitted] • A series of 24 phenylsulfonyl-pyrimidine carboxylate derivatives were designed and synthesized. • All compounds showed moderate to excellent in vitro inhibitory activity against AChE and BuChE at nanomolar concentration. • Two compounds BS-10 and BS-22 exhibited promising AChE inhibition. • Highlighted compounds BS-10 and BS-22 significantly inhibited Aβ aggregation. • BS-10 and BS-22 displayed high potential for BBB permeability. • BS-10 and BS-22 exhibited significant neuroprotection towards MC65 cells while no neurotoxicity. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as 1H NMR, 13C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a , 3e , 3f , 3g , 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC 50 value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC 50 = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC 50 = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies. Image 1 • 10 New thiazole derivatives including methyl sulfonyl scaffolds were synthesized. • All synthesized compounds showed selective COX-2 enzyme inhibition potency. • The compound 3a indicated important inhibitory activity against COX-2 enzyme. • A good ADME profile was predicted for all compounds. • Interaction modes between the COX-2 and compound 3a were determined by docking studies. [ABSTRACT FROM AUTHOR]

Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability. Image 1 • A new selective PDE4A and PDE4D inhibitor. • Good drug-like properties. • Blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. • relaxant effects on guinea pig trachea. [ABSTRACT FROM AUTHOR]

The burst of reactive oxygen species (ROS) contributes to and exacerbates cardiac injury. Exogenous supplementation of antioxidants or upregulation of endogenous antioxidant defense genes should be the potential therapies for cardiovascular disease. Sixteen coumarin-derived imino sulfonates compounds were synthesized with the ability of attenuating oxidative stress directly by reducing intracellular ROS level via promoting Nrf2 pathway. The cell-based assays showed that most of the compounds had significant protective activity against H 2 O 2 -induced oxidative injury in H9c2 cells. Compound 5h with the highest activity and low cytotoxicity was demonstrated to remarkably remove the intracellular ROS accumulation by activating expressions of Nrf2 and its downstream antioxidant proteins (ie. HO-1 and NQO1), indicating a novel promising antioxidant and Nrf2 activator. Overall, these findings demonstrated that compound 5h could serve as a potential cardioprotective agent. Moreover, our study features developing new antioxidants and Nrf2 activators by introducing a sulfonyl group and nitrogen atom to the α , β -unsaturated carbonyl entity in coumarin, rather than adding new functional groups or active fragments to coumarin itself. Image 1 • Sixteen coumarin-derived imino sulfonates were synthesized and characterized. • Most compounds displayed potent cardioprotective activities with low cytotoxicity. • 5h attenuated the oxidative stress via promoting Nrf2 pathway in cardiomyocytes. [ABSTRACT FROM AUTHOR]