Tag: M.W=200-250

Wang, Zhao published the artcileDiscovery of Novel Dihydrothiopyrano[4,3-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles, SDS of cas: 73874-95-0, the main research area is antiHIV antiviral resistance HIV1 infection hERG inhibition.

Enlightened by the available structural biol. information, a novel series of dihydrothiopyrano[4,3-d]pyrimidine derivatives were rationally designed via scaffold hopping and mol. hybridization strategies. Notably, compound 20a yielded exceptionally potent antiviral activities (EC50 = 4.44-54.5 nM) against various HIV-1 strains and improved resistance profiles (RF = 0.5-5.6) compared to etravirine and rilpivirine. Meanwhile, 20a exhibited reduced cytotoxicity (CC50 = 284μM) and higher SI values (SI = 5210-63992). Mol. dynamics simulations were performed to rationalize the distinct resistance profiles. Besides, 20a displayed better solubility (soluble = 12.8μg/mL) and no significant inhibition of the main CYP enzymes. Furthermore, 20a was characterized for prominent metabolic stability and in vivo safety properties. Most importantly, the hERG inhibition profile of 20a (IC50 = 19.84μM) was a remarkable improvement. Overall, 20a possesses huge potential to serve as a promising drug candidate due to its excellent potency, low toxicity, and favorable drug-like properties.

Journal of Medicinal Chemistry published new progress about Anti-HIV agents. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, SDS of cas: 73874-95-0.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Kang, Dongwei published the artcileDiscovery of potent HIV-1 non-nucleoside reverse transcriptase inhibitors by exploring the structure-activity relationship of solvent-exposed regions I, Name: tert-Butyl piperidin-4-ylcarbamate, the main research area is HIV 1 antiHIV non nucleoside reverse transcriptase; DAPY; HIV-1; NNRTIs; solvent-exposed region I; thiophene[3,2-d]pyrimidine.

Two novel series of human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) bearing a thiophene[3,2-d]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild-type (WT) HIV-1 strain in MT-4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV-1. Compound 7(I) (EC50 = 0.014, 0.031 μM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine (NVP, EC50 = 7.572, 0.190 μM) and comparable to that of etravirine (ETV, EC50 = 0.004, 0.014 μM). Mol. docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization.

Chemical Biology & Drug Design published new progress about Anti-HIV agents. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Name: tert-Butyl piperidin-4-ylcarbamate.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Manz, Theresa D. published the artcileStructure-Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors, Related Products of piperidines, the main research area is phosphatidylinositol 5 phosphate 4 kinase inhibitor THZP12 PI5P4K.

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are important mol. players in a variety of diseases, such as cancer. Currently available PI5P4K inhibitors are reversible small mols., which may lack selectivity and sufficient cellular on-target activity. In this study, we present a new class of covalent pan-PI5P4K inhibitors with potent biochem. and cellular activity. Our designs are based on THZ-P1-2, a covalent PI5P4K inhibitor previously developed in our laboratory Here, we report further structure-guided optimization and structure-activity relationship (SAR) study of this scaffold, resulting in compound 30(I), which retained biochem. and cellular potency, while demonstrating a significantly improved selectivity profile. Furthermore, we confirm that the inhibitors show efficient binding affinity in the context of HEK 293T cells using isothermal CETSA methods. Taken together, I represents a highly selective pan-PI5P4K covalent lead mol.

ACS Medicinal Chemistry Letters published new progress about Drug discovery. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Related Products of piperidines.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Buravchenko, Galina I. published the artcileDiscovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency, Quality Control of 73874-95-0, the main research area is amino phenylquinoxaline carbonitrile dioxide preparation anticancer antiestrogenic activity; Antiestrogenic potency; Antiproliferative activity; ERK 1/2 signaling pathway; HIF-1α; Hypoxia selectivity; Quinoxaline-2-carbonitrile 1,4-dioxide.

The synthesis of 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides bearing cyclic diamine residues at positions 6 or 7 I (R = H, piperazin-1-yl, 3-methylpiperazin-1-yl, 3-aminopyrrolidin-1-yl, etc.; R1 = F, Cl, 3-methylpiperazin-1-yl, etc.) based on the nucleophilic substitution of halogens has been described. All synthesized 6(7)-aminoquinoxaline-2-carbonitrile 1,4-dioxides I demonstrated higher cytotoxicity and hypoxia selectivity compared to the reference agent tirapazamine against breast adenocarcinoma cell lines (MCF7, MDA-MB-231). The structure and position of the diamine residue considerably affect the antiproliferative properties of the quinoxaline-2-carbonitrile 1,4-dioxides I. The introduction of a halogen atom at position 7 in the quinoxaline ring of I (R = piperazin-1-yl; R1 = H) considerably increases the cytotoxicity of compounds I [R = piperazin-1-yl; R1 = F, Cl] under both normoxic and hypoxic conditions. However, the most hypoxia-selective derivatives were non-halogenated 7-aminosubstituted 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides I (R = H; R1 = piperazin-1-yl, 3-methylpiperazin-1-yl, 3-aminopyrrolidin-1-yl, etc.). Of the 32 novel synthesized derivatives, I approx. some of the 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides demonstrated high antiproliferative potency against wild type leukemia cells K562 and drug-resistant subline K562/4 with the expression of p-glycoprotein (p-gp) compared to the reference agent doxorubicin, which exhibited one order of magnitude lower activity towards K562/4 cells than towards K562 cells. Lead compounds I (R = piperazin-1-yl; R1 = F) and I [R = H; R1 = (3S)-3-aminopyrrolidin-1-yl] inhibited HIF-1α expression and activity and induced apoptosis in hypoxic tumor cells, which was confirmed by poly(ADP-ribose)polymerase (PARP) cleavage. Moreover, I (R = piperazin-1-yl; R1 = F) and I [R = H; R1 = (3S)-3-aminopyrrolidin-1-yl] showed strong antiestrogenic potencies in MCF7 breast cancer cells. Thus, the described series of quinoxaline 1,4-dioxides I has high anticancer potential and good aqueous solubility Therefore, these compounds are promising for further drug development of hypoxia-targeted anticancer agents.

Bioorganic Chemistry published new progress about Antiestrogens. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Quality Control of 73874-95-0.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Blank, Brian R. published the artcileAntimalarial Trioxolanes with Superior Drug-Like Properties and In Vivo Efficacy, Name: tert-Butyl piperidin-4-ylcarbamate, the main research area is antimalarials endoperoxides trioxolanes lead optimization stereoselective synthesis; antimalarials; endoperoxides; lead optimization; stereoselective synthesis; trioxolanes.

The emergence of artemisinin resistance, combined with certain suboptimal properties of ozonide agents arterolane and artefenomel, has necessitated the search for new drug candidates in the endoperoxide class. Our group has focused on trioxolane analogs with substitution patterns not previously explored. Here, we describe the enantioselective synthesis of analogs bearing a trans-3” carbamate side chain and find these to be superior, both in vitro and in vivo, to the previously reported amides. We identified multiple analogs that surpass the oral efficacy of arterolane in the Plasmodium berghei model while exhibiting drug-like properties (logD, solubility, metabolic stability) similar or superior to next-generation clin. candidates like E209 and OZ609. While the preclin. assessment of new analogs is still underway, current data suggest the potential of this chemotype as a likely source of future drug candidates from the endoperoxide class.

ACS Infectious Diseases published new progress about Antimalarials. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Name: tert-Butyl piperidin-4-ylcarbamate.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Serrano, Catherine M. published the artcileUnifying the Aminohexopyranose- and Peptidyl-Nucleoside Antibiotics: Implications for Antibiotic Design, Safety of tert-Butyl piperidin-4-ylcarbamate, the main research area is tuberculosis antiretroviral amicetin prokaryotic translation inhibitor; amicetin; antibiotic; blasticdin S; ribosome; translation inhibitor.

In search of new anti-tuberculars compatible with anti-retroviral therapy we re-identified amicetin as a lead compound Amicetin’s binding to the 70S ribosomal subunit of Thermus thermophilus (Tth) has been unambiguously determined by crystallog. and reveals it to occupy the peptidyl transferase center P-site of the ribosome. The amicetin binding site overlaps significantly with that of the well-known protein synthesis inhibitor balsticidin S. Amicetin, however, is the first compound structurally characterized to bind to the P-site with demonstrated selectivity for the inhibition of prokaryotic translation. The natural product-ribosome structure enabled the synthesis of simplified analogs that retained both potency and selectivity for the inhibition of prokaryotic translation.

Angewandte Chemie, International Edition published new progress about 70S ribosome. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Safety of tert-Butyl piperidin-4-ylcarbamate.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Brighty, Gabriel J. published the artcileUsing sulfuramidimidoyl fluorides that undergo sulfur(VI) fluoride exchange for inverse drug discovery, Name: tert-Butyl piperidin-4-ylcarbamate, the main research area is sulfuramidimidoyl fluoride preparation inverse drug discovery cancer.

Abstract: Drug candidates that form covalent linkages with their target proteins have been underexplored compared with the conventional counterparts that modulate biol. function by reversibly binding to proteins, in part due to concerns about off-target reactivity. However, toxicity linked to off-target reactivity can be minimized by using latent electrophiles that only become activated towards covalent bond formation on binding a specific protein. Here we study sulfuramidimidoyl fluorides, a class of weak electrophiles that undergo sulfur(VI) fluoride exchange chem. We show that equilibrium binding of a sulfuramidimidoyl fluoride to a protein can allow nucleophilic attack by a specific amino acid side chain, which leads to conjugate formation. We incubated small mols., each bearing a sulfuramidimidoyl fluoride electrophile, with human cell lysate, and the protein conjugates formed were identified by affinity chromatog.-mass spectrometry. This inverse drug discovery approach identified a compound that covalently binds to and irreversibly inhibits the activity of poly(ADP-ribose) polymerase 1, an important anticancer target in living cells. [graphic not available: see fulltext]

Nature Chemistry published new progress about Antitumor agents. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Name: tert-Butyl piperidin-4-ylcarbamate.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

El Abbouchi, Abdelmoula published the artcileSynthesis and biological evaluation of ethacrynic acid derivatives bearing sulfonamides as potent anti-cancer agents, Name: tert-Butyl piperidin-4-ylcarbamate, the main research area is ethacrynic acid sulfonamide preparation anticancer human safety; Anti-cancer; Anti-proliferative; Cancer cells; Ethacrynic acid; Safety ratios; Sulfonamides.

A series of ethacrynic acid (2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid) (EA, Edecrin) containing sulfonamides linked via three types of linkers namely 1,2-ethylenediamine, piperazine and 4-aminopiperidine was synthesized and subsequently evaluated in vitro against HL60 and HCT116 cancer cell lines. All the EA analogs, excluding two derivs, showed anti-proliferative activity with IC50s in the micromolar range (less than 4 uM). Three derivatives I-III were selected for their interesting dual activity on HL60 cell line in order to be further evaluated against a panel of cancer cell lines (HCT116, A549, MCF7, PC3, U87-MG and SKOV3) as well as on MRC5 as a normal cell line. These compounds displayed IC50 values in nanomolar range against A549, MCF7, PC3 and HCT116 cell lines, deducing the discovery that piperazine or 4-aminopiperidine is the linker’s best choice to develop EA analogs with highly potent anti-proliferative activities own up to 24 nM. Besides, in terms of selectivity, those linkers are more suitable offering safety ratios of up to 63.8.

Bioorganic & Medicinal Chemistry Letters published new progress about Antitumor agents. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Name: tert-Butyl piperidin-4-ylcarbamate.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Dimitrov, Teodor published the artcileDevelopment of novel urea-based ATM kinase inhibitors with subnanomolar cellular potency and high kinome selectivity, Recommanded Product: tert-Butyl piperidin-4-ylcarbamate, the main research area is urea ATM kinase inhibitor subnanomolar cellular potency kinome selectivity; ATM kinase; ATM kinase inhibitors; Cancer; DDR pathway; MD simulation; PIKK.

The ATM kinase is a key mol. regulating DNA damage response and can be targeted resulting in efficient radio- or chemosensitization. Due to the enormous size of this protein and the associated difficulties in obtaining high-quality crystal structures, we sought to develop an accurate in silico model to identify new targeting possibilities. We identified a urea group as the most beneficial chem. anchor point, which could undergo multiple interactions in the aspartate-rich hydrophobic region I of the atypical ATM kinase domain. Based on in silico data, we designed and synthesized a comprehensive set of novel urea-based inhibitors and characterized them in diverse biochem. assays. Using this strategy, we identified inhibitors with subnanomolar potency, which were further evaluated in cellular models, selectivity and early DMPK properties. Finally, the two lead compounds 34 and 39 exhibited subnanomolar cellular activity along with an excellent selectivity profile and favorable metabolic stability.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Recommanded Product: tert-Butyl piperidin-4-ylcarbamate.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Liu, Wen-Shan published the artcileDesign, synthesis and biological evaluation of pyridine derivatives as selective SHP2 inhibitors, SDS of cas: 73874-95-0, the main research area is tumor SHP2 inhibitor scaffold hopping ADMET mol docking binding; ADMET; Activity; Molecular docking; SHP2 inhibitor; Scaffold hopping.

SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which affects the transduction of multiple signaling pathways, including RAS-ERK, PI3K-AKT and JAK-STAT. SHP2 also plays an important role in the programmed cell death pathway (PD-1/PD-L1). Studies have shown that SHP2 is associated with a variety of cancers, including breast, liver and gastric cancers. Therefore, the development of SHP2 inhibitors has attracted extensive attention. In this study, based on the known inhibitor 1 (SHP099), novel SHP2 inhibitors were designed by means of scaffold hopping, and 35 pyridine derivatives as SHP2 inhibitors were found. The in vitro enzyme activity assay was performed on these compounds, and multiple selective SHP2 inhibitors with activity potency similar to that of SHP099 were obtained. Among them, compound (2-(4-(aminomethyl)piperidin-1-yl)-5-(2,3-dichlorophenyl)pyridin-3-yl)methanol (11a) was the most potent and highly selective SHP2 inhibitor with an in vitro enzyme activity IC50 value of 1.36 μM. Fluorescence titration assay verified that 11a bound directly to SHP2 protein. Subsequently, cell assay of representative compounds showed that these compounds could effectively inhibit the proliferation of Ba/F3 cells. In addition, the pharmacokinetic characteristics of the designed compounds were analyzed by the in silico ADMET prediction. Mol. docking study provided more detailed information on the binding mode of compounds and SHP2 protein. In brief, this study reported for the first time that pyridine derivatives as novel SHP2 inhibitors had good inhibitory activity and selectivity, providing new clues for the development of small mol. SHP2 inhibitors.

Bioorganic Chemistry published new progress about Antitumor agents. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, SDS of cas: 73874-95-0.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem