gamma-Non-symmetrically-dimasked TriPPPro-prodrugs as potential antivirals against HIV.
Abstract Nucleoside analogue reverse transcriptase inhibitors (NRTI) and nucleoside analogue monophosphate prodrugs are used in combination antiretroviral therapy (cART). The design of antivirally active nucleoside triphosphate prodrugs is a recent and an important advancement in the field of nucleoside analogue drug development. Here, we report on Tri PPP ro-derivatives of nucleoside analogue triphosphates (NTPs) that comprised two different acyloxybenzyl-masks at the γ-phosphate of the NTP aiming to achieve the metabolic bypass. Thus, γ-non-symmetrically dimasked Tri PPP ro-compounds (γ-(AB,ab)...
Source: ChemMedChem - October 22, 2020 Category: Chemistry Authors: Zhao C, Jia X, Schols D, Balzarini J, Meier C Tags: ChemMedChem Source Type: research

The Stone Guest: How Does pH Affect Binding Properties of PD-1/PD-L1 Inhibitors ?
In this study, we have investigated the effect of pH shifts on binding properties of distinct classes of PD-L1 inhibitors, including macrocyclic peptide and small molecules. Results expand structure-activity relationships of PD-L1 inhibitors, providing insights into structural features and physicochemical properties that are useful for the design of ligands that may escape a drug resistance mechanism associated to variable pH conditions of tumor microenvironment. PMID: 33085193 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - October 21, 2020 Category: Chemistry Authors: Riccio A, Coletti A, Dolciami D, Mammoli A, Cerra B, Moretti S, Gioiello A, Ferlin S, Puxeddu E, Macchiarulo A Tags: ChemMedChem Source Type: research

Novel Phenylmethylenecyclohexenone Derivatives as Potent TrxR Inhibitors Display High Antiproliferative Activity and Induce ROS, Apoptosis, and DNA Damage.
In conclusion, 10e, with prominent tumor selectivity and water solubility, could be a promising candidate for the treatment of cancer and, as such, warrants further investigation. PMID: 33085980 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - October 21, 2020 Category: Chemistry Authors: Wang X, Qian J, Zhu P, Hua R, Liu J, Hang J, Meng C, Shan W, Miao J, Ling Y Tags: ChemMedChem Source Type: research

Stereoselective Synthesis and Antiallodynic Activity of 3-Hydroxylated Paroxetines.
ero L Abstract The design, stereoselective synthesis and in vivo antiallodynic activity of four novel paroxetine analogs, named 3-hydroxy paroxetines (3HPXs), is reported.  Among the novel synthesized compounds, three of them showed antiallodynic effect, while the ( R , R )-3HPX resulted to be 2.5 times more bioactive than (-)-paroxetine itself in neuropathic rats. Consequently, the current investigation not only discloses a novel promising analgesic drug , but also reveals that functionalization at the C-3 position of paroxetine could be as effective as the common functionalization at either C-4 or within th...
Source: ChemMedChem - October 19, 2020 Category: Chemistry Authors: Sartillo-Piscil F, Chamorro-Arenas D, Salgado-Moreno G, Martinez-Mendieta L, Godínez-Chaparro B, Quintero L Tags: ChemMedChem Source Type: research

Synthesis and structure-activity relationships of imidazopyridine/pyrimidine- and furopyridine-based anti-infective agents against trypanosomiases.
We report on a set of 57 heterocyclic compounds with selective activity potential against kinetoplastid parasites. In general, 30 and 19 compounds of the total set could be defined as active against Trypanosoma cruzi and T. brucei brucei , respectively (antitrypanosomal activities
Source: ChemMedChem - October 19, 2020 Category: Chemistry Authors: Silva DG, Junker A, de Melo SMG, Fumagalli F, Gillespie JR, Molasky N, Buckner FS, Matheeussen A, Caljon G, Maes L, Emery FS Tags: ChemMedChem Source Type: research

Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing.
LR Abstract Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody-drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non-pathological cells proximal to the tumour ("bystander killing"). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz-azastatin methyl ester, which included the C2-elongation and diastereoselective reduction of two proteinogenic...
Source: ChemMedChem - October 16, 2020 Category: Chemistry Authors: Hartmann RW, Fahrner R, Shevshenko D, Fyrknäs M, Larsson R, Lehmann F, Odell LR Tags: ChemMedChem Source Type: research

Memoirs of the First 50 Years of the European Federation for Medicinal Chemistry (EFMC).
Abstract These memoirs span the first fifty years of the European Federation for Medicinal Chemistry (EFMC). They are the personal observations and remembrance of Prof. Henk Timmerman, who witnessed how the EFMC developed since its inception in December 1969, and are published at the occasion of the 50th anniversary of the EFMC. They include, with permission from the EFMC, material that was previously published in EFMC newsletters. These texts are for the first time united and completed, to tell the history of an organization that has accompanied and shaped the development of medicinal chemistry in Europe. They al...
Source: ChemMedChem - October 16, 2020 Category: Chemistry Authors: Timmerman H Tags: ChemMedChem Source Type: research

An Integrated In Silico Approach and In Vitro Study for the Discovery of USP7 Small Molecule Inhibitors as Potential Cancer Therapies.
In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ~ 220.000 drug-like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1-ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 ligands. Based on their MM/GBSA analysis, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a pos...
Source: ChemMedChem - October 16, 2020 Category: Chemistry Authors: Kanan D, Kanan T, Dogan B, Orhan MD, Avsar T, Durdagi S Tags: ChemMedChem Source Type: research

Broad-Spectrum Antifungal Agents: Fluorinated Aryl- and Heteroaryl-Substituted Hydrazones.
Abstract Fluorinated aryl- and heteroaryl-substituted monohydrazones displayed excellent broad-spectrum activity against various fungal strains, including a panel of clinically relevant Candida auris strains relative to a control antifungal agent, voriconazole (VRC). These monohydrazones displayed less hemolysis of murine red blood cells than that of VRC at the same concentrations, possessed fungicidal activity in a time-kill study, and exhibited no mammalian cell cytotoxicity. In addition, these monohydrazones prevented the formation of biofilms that otherwise block antibiotic effectiveness and did not trigger th...
Source: ChemMedChem - October 16, 2020 Category: Chemistry Authors: Thamban Chandrika N, Dennis EK, Brubaker KR, Kwiatkowski S, Watt DS, Garneau-Tsodikova S Tags: ChemMedChem Source Type: research

Multitarget inhibition of histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K): Current and future prospects.
Abstract The discovery of HDACs inhibitors is a hot topic in the medicinal chemistry community regarding cancer research, which is related primarily to two factors: success in the clinics, e.g., the four FDA-approved HDAC inhibitors, and strong versatility to combine their pharmacophoric features to design new hybrid compounds with multitarget profile. Thus, selecting adequate pharmacophores to combine, i.e., combining targets that can result in a synergistic effect, is desirable, since it will increase the probability of discovering a new useful therapeutic strategy. In this work, we highlight the design of multi...
Source: ChemMedChem - October 13, 2020 Category: Chemistry Authors: Fraga CAM, Rodrigues DA, Pinheiro PSM Tags: ChemMedChem Source Type: research

Co-staining of KCa3.1 channels in NSCLC cells with a small-molecule fluorescent probe and antibody-based indirect immunofluorescence.
chwab A Abstract The Ca 2+  activated potassium channel 3.1 (K Ca 3.1) is involved in critical steps of the metastatic cascade, such as proliferation, migration, invasion and extravasation. Therefore, a fast and efficient protocol for imaging of K Ca 3.1 channels was envisaged. The fluorescently labeled small molecule imaging probes 1 and 2 were synthesized by connecting a dimethylpyrrole-based BODIPY dye with a derivative of the K Ca 3.1 channel inhibitor senicapoc via linkers of different length. Patch-clamp experiments revealed the inhibition of K Ca 3.1 channels by the probes confirming interaction with t...
Source: ChemMedChem - October 12, 2020 Category: Chemistry Authors: Wünsch B, Brömmel K, Maskri S, Bulk E, Pethő Z, Rieke M, Budde T, Koch O, Schwab A Tags: ChemMedChem Source Type: research

A Comprehensive Overview of Structure-Activity Relationships of Small-Molecule Splicing Modulators Targeting SF3B1 as Anticancer Agents.
Abstract The pre-mRNA splicing factor SF3B1 shows recurrent mutations among hematologic malignancies and some solid tumors. In 2007, the identification of two cytotoxic natural products, which showed splicing inhibition by binding to SF3b, prompted the development of small-molecule splicing modulators of SF3B1 as therapeutics for cancer. Recent study suggested that spliceosome-mutant cells are preferentially sensitive to pharmacologic splicing modulation, therefore, exploring the clinical utility of splicing modulator therapies in patients with spliceosome-mutant hematologic malignancies who have failed current th...
Source: ChemMedChem - October 9, 2020 Category: Chemistry Authors: Zhang D, Meng F Tags: ChemMedChem Source Type: research

Two Methods, one Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses.
Abstract In lead optimization, protein crystallography is an indispensable tool to analyze drug binding. Binding modes and non-covalent interaction inventories are essential to design follow-up synthesis candidates. Two protocols are commonly applied to produce protein-ligand complexes: cocrystallization and soaking. Because of its time and cost effectiveness, soaking is the more popular method. Taking eight ligand hinge binders of protein kinase A, we demonstrate that cocrystallization is superior. Particularly for flexible proteins, such as kinases, and larger ligands cocrystallization captures more reliable the...
Source: ChemMedChem - October 8, 2020 Category: Chemistry Authors: Klebe G, Wienen-Schmidt B, Oebbeke M, Ngo K, Heine A Tags: ChemMedChem Source Type: research

A New Series of Ferulic Acid Amides Reveals an Unexpected Peroxiredoxin 1 Inhibition Activity With In Vivo Antidiabetic and Hypolipidemic Effects.
a A Abstract Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considered as ring opening derivatives of the antidiabetic PPARγ agonists Thiazolidinediones (TZDs). However, since these compounds displayed weak PPAR transactivation capacity, we employed a proteomics approach to unravel their molecular target(s) and identified the peroxiredoxin 1 (PRDX1) ...
Source: ChemMedChem - October 8, 2020 Category: Chemistry Authors: Yasmin S, Cerchia C, Badavath VN, Laghezza A, Dal Piaz F, Mondal SK, Atlı Ö, Baysal M, Vadivelan S, S S, Siddique MUM, Pattnaik AK, Singh RP, Loiodice F, Jayaprakash V, Lavecchia A Tags: ChemMedChem Source Type: research

A Single Second Shell Amino Acid Determines Affinity and Kinetics of Linagliptin Binding to Type 4 Dipeptidyl Peptidase and Fibroblast Activation Protein.
Abstract Type 4 dipeptidyl peptidase (DPP-4) and fibroblast activation protein alpha (FAP-α) are implicated in the pathophysiology of several metabolic disorders. Drugs targeting DPP-4 inhibition are beneficial for glycemic control, whereas FAP inhibition is a potential target for cancer therapies. In contrast to other gliptins, linagliptin displays unique FAP inhibition. We compared biophysical and structural mechanisms of linagliptin binding to DPP-4 and FAP. Linagliptin exhibited high binding affinity (K D ) and a slow off-rate (k off ) when dissociating from DPP-4 (K D 6.6 pM; k off 5.1 ´...
Source: ChemMedChem - October 8, 2020 Category: Chemistry Authors: Schnapp G, Hoevels Y, Bakker R, Schreiner P, Thomas K, Nar H Tags: ChemMedChem Source Type: research

2-Isoxazolines: A synthetic and medicinal overview.
Conclusion. PMID: 33029886 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - October 7, 2020 Category: Chemistry Authors: Shankar R, Kumar G Tags: ChemMedChem Source Type: research

Alternating Cationic-Hydrophobic Peptide/Peptoid Hybrids: Influence of Hydrophobicity on Antibacterial Activity and Cell Selectivity.
k H Abstract The influence of hydrophobicity on antibacterial activity versus the effect on the viability of mammalian cells for peptide/peptoid hybrids was examined for oligomers based on the cationic Lys-like peptoid residue combined with each of 28 hydrophobic amino acids in an alternating sequence. Their relative hydrophobicity was correlated to activity against both Gram-negative and Gram-positive species, human red blood cells, and HepG2 cells. This identified hydrophobic side chains that confer potent antibacterial activity (e. g., MICs of 2-8 μg/mL against E. coli) and low toxicity toward mamma...
Source: ChemMedChem - October 7, 2020 Category: Chemistry Authors: Frederiksen N, Hansen PR, Zabicka D, Tomczak M, Urbas M, Domraceva I, Björkling F, Franzyk H Tags: ChemMedChem Source Type: research

Gramicidin S-inspired Cyclopeptidomimetics as Potent Membrane-active Bactericidal Agents with Therapeutic Potential.
Abstract Antimicrobial peptides (AMPs) are promising antibacterial agents often hindered by their undesired hemolytic activity. Inspired by gramicidin S (GS), a well-known cyclodecapeptide, we synthesized a panel of antibacterial cyclopeptidomimetics using β,γ-diamino acids (β,γ-DiAAs). We observed that peptidomimetic CP-2 displays a bactericidal activity similar to that of GS while possessing lower side-effects. Moreover, extensive studies revealed that CP-2 likely kills bacteria through membrane disruption. Altogether, CP-2 is a promising membrane-active antibiotic with therapeutic potentia...
Source: ChemMedChem - October 7, 2020 Category: Chemistry Authors: Wan Y, Hu C, Wen Q, Huang S, Xie S, Fang Y, Jin Y, Campagne R, Alezra V, Miclet E, Zhu J Tags: ChemMedChem Source Type: research

Effect of Secondary Structure and Side Chain Length of Hydrophobic Amino Acid Residues on the Antimicrobial Activity and Toxicity of 14 Residue Long de novo AMPs.
This study showed that too long or short side chains increase the toxicity and lower the antimicrobial activity respectively. VV-14 was non-cytotoxic and highly potent in physiological salt concentrations against several pathogens, especially Salmonella typhi TY2 . The AMPs acted via membrane deformation, depolarisation and lysis. The activity of the AMPs was related to their ability of forming amphipathic helical conformation in the presence of microbial membrane mimics. Among AMPs with same charge, hydrophobic interaction in between the side chains of the amino acid residues with the membrane lipids determine their antim...
Source: ChemMedChem - October 7, 2020 Category: Chemistry Authors: Chatterjee S, Pandit G, Chowdhury N, Mohid SA, Bidkar AP, Bhunia A Tags: ChemMedChem Source Type: research

Tricepyridinium-inspired QACs yield potent antimicrobials and provide insight into QAC resistance.
Abstract Quaternary ammonium compounds (QACs) comprise a large class of surfactants, consumer products, and disinfectants. The recently-isolated QAC natural product tricepyridinium bromide displays potent inhibitory activity against S. aureus but due to its unique structure, its mechanism of action remains unclear. A concise synthetic route to access tricepyridinium analogs was thus designed and four N-alkyl compounds were generated in addition to the natural product. Biological analysis of these compounds revealed that they display remarkable selectivity towards clinically-relevant Gram-positive bacteria exceedin...
Source: ChemMedChem - October 7, 2020 Category: Chemistry Authors: Garrison MA, Mahoney AR, Wuest WM Tags: ChemMedChem Source Type: research

Mechanism Toward Turn-on of Polysaccharide-Porphyrin Complexes for Fluorescence Probes and Photosensitizers in Photodynamic Therapy in Living Cells.
Abstract β-(1,3-1,6)-D-Glucan, λ-carrageenan, tamarind gum, and pullulan can dissolve various porphyrin derivatives via the formation of complexes in water using a high-speed vibration milling method. The aqueous solutions of the resulting complexes exhibit long-term stability. Despite the adverse effects of the self-quenching process, notable fluorescence and improved photodynamic activity of the polysaccharide-complexed porphyrin derivatives were observed in the presence of liposomes, micelles, cyclodextrins, and HeLa cells. It was noted that the type of porphyrins was more important than the type of...
Source: ChemMedChem - October 6, 2020 Category: Chemistry Authors: Hino S, Funada R, Sugikawa K, Kawasaki R, Koumoto K, Suzuki T, Nagasaki T, Ikeda A Tags: ChemMedChem Source Type: research

Gold Drugs with {Au(PPh3)}+ moiety: Advantages and Medicinal Applications.
Abstract Following the success of Auranofin as an anti-arthritic drug, search for novel gold drugs has afforded a large number of [L-Au(PPh 3 )] complexes that exhibit notable salutary effects. Unlike Au(III)-containing species, these gold complexes with {Au(PPh 3 )} + moiety are stable in biological media and readily exchange L with S- and Se-containing enzymes or proteins. Such exchange leads to rapid reduction of microbial loads or induction of apoptotic cell death at malignant sites. In many cases the lipophilic {Au(PPh 3 )} + moiety delivers a desirable toxic L to the specific cellular target in addition to e...
Source: ChemMedChem - October 6, 2020 Category: Chemistry Authors: Mascharak P, Stenger-Smith J Tags: ChemMedChem Source Type: research

Synthesis and evaluation of voltage-gated sodium channel blocking pyrroline derivatives endowed with both antiarrhythmic   and antioxidant activities.
Synthesis and evaluation of voltage-gated sodium channel blocking pyrroline derivatives endowed with both antiarrhythmic  and antioxidant activities. ChemMedChem. 2020 Oct 04;: Authors: Carocci A, Budriesi R, Micucci M, Cavalluzzi MM, Milani G, Catalano A, De Palma A, Corbo F, Franchini C, Habtemariam S, Giovanni L Abstract Under the hypothesis that cardioprotecting agents might benefit from a synergism between antiarrhythmic activity and antioxidant properties, a small series of mexiletine analogues were coupled with the 2,2,5,5-tetramethylpyrroline moiety, known for its antioxidant effect, in o...
Source: ChemMedChem - October 3, 2020 Category: Chemistry Authors: Carocci A, Budriesi R, Micucci M, Cavalluzzi MM, Milani G, Catalano A, De Palma A, Corbo F, Franchini C, Habtemariam S, Giovanni L Tags: ChemMedChem Source Type: research

An Advanced Apralog with Increased in-vitro and in-vivo Activity toward Gram-negative Pathogens and Reduced ex-vivo Cochleotoxicity.
We describe the convergent synthesis of a 5-O-β-D-ribofuranosyl-based apramycin derivative (apralog) that displays significantly improved antibacterial activity over the parent apramycin against wild-type ESKAPE pathogens.  In addition, the new apralog retains excellent antibacterial activity in the presence of the only aminoglycoside modifying enzyme (AAC(3)-IV) acting on the parent, without incurring susceptibility to the APH(3') mechanism that disables other 5-O-β-D-ribosfuranosyl 2-deoxystreptamine type aminoglycosides by phosphorylation at the ribose 5-position.  Consistent with this antibacterial ...
Source: ChemMedChem - October 1, 2020 Category: Chemistry Authors: Crich D, Sonousi A, Quirke J, Waduge P, Janusic T, Gysin M, Haldimann K, Hobbie S, Sha SH, Schacht J, Christine C, Andrea V, Bottger EC, Xu S Tags: ChemMedChem Source Type: research

Targeted Protein Degradation as a Promising Tool for Epigenetic  Upregulation of Fetal Hemoglobin.
Targeted Protein Degradation as a Promising Tool for Epigenetic Upregulation of Fetal Hemoglobin. ChemMedChem. 2020 Oct 01;: Authors: Verheul TCJ, Trinh VT, Vazquez O, Philipsen S Abstract The level of fetal hemoglobin (HbF) is an important disease modifier for b-thalassemia and sickle cell disease patients. Indeed, genetic tinkering with the HbF repression machinery has demonstrated great potential for disease mitigation. Such genetic treatments are costly and the high incidence of b-hemoglobinopathies in low-income countries therefore calls for the development of a...
Source: ChemMedChem - September 30, 2020 Category: Chemistry Authors: Verheul TCJ, Trinh VT, Vazquez O, Philipsen S Tags: ChemMedChem Source Type: research

Bisubstrate ether-linked uridine-peptide conjugates as O-GlcNAc transferase inhibitors.
We report linear bisubstrate ether-linked uridine-peptide conjugates as OGT inhibitors having micromolar affinity. In vitro evaluation of the compounds revealed the importance of donor substrate, linker and acceptor substrate in the rational design of bisubstrate analogue inhibitors. Molecular dynamics simulations shed light on the binding of this novel class of inhibitors and rationalized the effect of amino acid truncation of acceptor peptide on OGT inhibition. PMID: 32991074 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - September 28, 2020 Category: Chemistry Authors: Rudrawar S, Makwana V, Ryan P, Malde AK, Anoopkumar-Dukie S Tags: ChemMedChem Source Type: research

Evaluation of a Platinum-Acridine Anticancer Agent and Its Liposomal Formulation in an In Vivo Model of Lung Adenocarcinoma.
Abstract Liposomal formulations have been developed for a highly cytotoxic platinum-acridine agent, [PtCl(pn)(C 18 H 21 N 4 )](NO 3 ) 2 ( PA , pn = propane-1,3-diamine), and fully characterized.   Nanoliposomes consisting of hydrogenated soybean phosphatidylcholine (HSPC), 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1´-rac-glycerol) (DPPG), and polyethylene glycol-2000-distearoylphosphatidylethanolamine (DSPE-mPEG 2k ) were able to stably encapsulate PA at payload-to-lipid ratios of 2-20%.  The fusogenic properties of the liposomes promote efficient cellular uptake of PA across the plasma membran...
Source: ChemMedChem - September 23, 2020 Category: Chemistry Authors: Ding S, Hackett CL, Liu F, Hackett RG, Bierbach U Tags: ChemMedChem Source Type: research

Development of novel selective TGR5 ligands based on 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphtaklene skeleton.
In this study, we designed and synthesized a set of TGR5 ligands with a TMN (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene) skeleton, and evaluated their TGR5 agonistic activity. Moreover, we also investigated the selectivity of the synthesized compounds to TGR5 compared to Farnesoid X receptor (FXR) and retinoic acid receptor (RAR). Our results showed that compound 4b exhibited a potent TGR5 agonist activity with an IC50 value of 8.4 nM without any significant cytotoxicity. In addition, compound 4b showed only slight agonistic activity to FXR and RAR at 1 mM treatment. These data indicated that compound 4b is a select...
Source: ChemMedChem - September 22, 2020 Category: Chemistry Authors: Terui R, Yanase Y, Yokoo H, Suhara Y, Makishima M, Demizu Y, Misawa T Tags: ChemMedChem Source Type: research

Benzylaminoethylureido-tailed benzenesulfonamides show potent inhibitory action against bacterial carbonic anhydrases.
Abstract A series of benzylaminoethylureido-tailed benzenesulfonamides was analyzed for their inhibition potential against bacterial carbonic anhydrases (CAs) such as VhCA α, β, and γ from Vibrio cholerae , and BpsCA β and γ-CAs from Burkholderia pseudomallei . Growing drug-resistance against antibiotics demands alternative targets and mechanisms of action. As CA is essential for the survival of bacteria, such enzymes have the potential for developing new antibiotics. Most of the compounds presented excellent inhibition potential against VhCA γ as compared to α and β, w...
Source: ChemMedChem - September 22, 2020 Category: Chemistry Authors: Ali M, Bozdag M, Angeli A, Carta F, Capasso C, Farooq U, Supuran CT Tags: ChemMedChem Source Type: research

Red Emissive Carbon Dots Prepared from Polymers as An Efficient Nanocarrier for Coptisine Delivery In Vivo and In Vitro.
Abstract Negatively charged fluorescent carbon dots (CDs, E m =608 nm) were hydrothermally prepared from thiophene phenylpropionic acid polymers and then successfully loaded with the positively charged anticancer cargo coptisine, which suffers from poor bioavailability. The formed CDs-Coptisine complexes were thoroughly characterized by particle size, morphology, drug loading efficiency, drug release, cellular uptake and cellular toxicity in vitro  and anti-tumor activities in vivo . In this nano-carrier system, red emissive CDs possesses multiple advantages as follows: 1) high drug loading efficiency (>96...
Source: ChemMedChem - September 21, 2020 Category: Chemistry Authors: Ren W, Nan F, Li S, Yang S, Ge J, Zhao Z Tags: ChemMedChem Source Type: research

Broad-spectrum Flavivirus Inhibitors: a Medicinal Chemistry Point of View.
Abstract Infections by flaviviruses, such as Dengue, West Nile, Yellow Fever and Zika viruses, represent a growing risk for global health. There are vaccines only for few flaviviruses while no effective treatments are available. Flaviviruses share epidemiological, structural, and ecologic features and often different viruses can co-infect the same host. Therefore, the identification of broad-spectrum inhibitors is highly desirable either for known flaviviruses or for viruses that likely will emerge in the future. Strategies targeting both virus and host factors have been pursued to identify broad-spectrum antiflav...
Source: ChemMedChem - September 21, 2020 Category: Chemistry Authors: Felicetti T, Manfroni G, Cecchetti V, Cannalire R Tags: ChemMedChem Source Type: research

Novel BODIPY-based photosensitizers as potential anticancer and antibacterial agents: The role of the positive charge and the heavy atom effect.
Abstract Boron-dipyrromethene derivatives including cationic and iodinated analogs were obtained and subjected to physicochemical and in vitro photodynamic activity studies. Iodinated derivatives revealed a substantial heavy atom effect manifested by a bathochromic shift of the absorption band by about 30 nm and fluorescence intensity reduced by about 30-35 times, compared to that obtained for non-iodinated ones. In consequence, singlet oxygen generation significantly increased with Φ Δ values in the range 0.69-0.97. The in vitro photodynamic activity was evaluated on Gram-positive Staphylococcus aureus,...
Source: ChemMedChem - September 19, 2020 Category: Chemistry Authors: Piskorz J, Porolnik W, Kucinska M, Dlugaszewska J, Murias M, Mielcarek J Tags: ChemMedChem Source Type: research

A Structure-Activity Relationship Study of Novel Hydroxamic Acid Inhibitors around the S1 Subsite of Human Aminopeptidase N.
Abstract Aminopeptidase N (APN/CD13) is a zinc-dependent ubiquitous transmembrane ectoenzyme that is widely present in different types of cells. APN is one of the most extensively studied metalloaminopeptidases as an anti-cancer target due to its significant role in the regulation of metastasis and angiogenesis. Previously we identified a potent and selective APN inhibitor, N-(2-(hydroxyamino)-2-oxo-1-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (3). Herein, we report the further modifications performed to explore SAR around the S1 subsite of APN and to improve the physicochemical...
Source: ChemMedChem - September 17, 2020 Category: Chemistry Authors: Scammells PJ, Lee J, Drinkwater N, McGowan S Tags: ChemMedChem Source Type: research

Sulfonamide Inhibitors of ß-Catenin Signaling with Different Output on c-MYC as Anticancer Agents.
Sulfonamide Inhibitors of ß-Catenin Signaling with Different Output on c-MYC as Anticancer Agents. ChemMedChem. 2020 Sep 18;: Authors: Silvestri R, Di Magno L, Di Pastena F, Puxeddu M, La Regina G, Coluccia A, Ciogli A, Manetto S, Maroder M, Canettieri G, Nalli M Abstract The Wnt/ β -catenin pathway is often found deregulated in cancer. The aberrant accumulation of  β -catenin in the cell nucleus results in the development of various malignancies. Specific drugs against this signaling pathway for clinical treatments have not been approved yet. Here we report inhibitors o...
Source: ChemMedChem - September 17, 2020 Category: Chemistry Authors: Silvestri R, Di Magno L, Di Pastena F, Puxeddu M, La Regina G, Coluccia A, Ciogli A, Manetto S, Maroder M, Canettieri G, Nalli M Tags: ChemMedChem Source Type: research

Synthesis and structure-activity relationship of 3-arylisoquinolone analogues as novel highly specific hCES2A inhibitors.
In this study, 3-arylisoquinolone 3h was found with potent inhibitory effect on hCES2A (IC 50 = 0.68 μΜ, K i =0.36 μΜ) and excellent specificity (more than 147.05 fold over hCES1A). Moreover, brominated product 4a exhibited 3-fold improvement inhibition on intracellular hCES2A in living HepG2 cells compared with 3h , with the IC 50 value of 0.41 μΜ. The inhibition kinetics results and molecular docking simulations demonstrated that both 3h and 4a could bind to multiple sites of hCES2A, functioning as mixed inhibitors. The SAR (structure-activity relationship) analysis revealed that the lactam moiety on B ...
Source: ChemMedChem - September 15, 2020 Category: Chemistry Authors: Li B, Zhao Y, Xiong Y, Dong S, Guan X, Song Y, Yang Y, Zou K, Li Z, Zhang Y, Fang S, Zhu W, Chen K, Jia Q, Ge G Tags: ChemMedChem Source Type: research

Radiosynthesis and preclinical investigation of 11C labelled 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime ([11C]SZV 1287).
;lai T, Trencsényi G, Fekete A, Szikra D Abstract The radiosynthesis, as well as the in vivo and ex vivo biodistribution of the 11 C radiolabelled 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime ( 6 , [ 11 C]SZV 1287) are reported. SZV 1287 is a novel SSAO inhibitor and a promising candidate to be a novel analgesic for the treatment of neuropathic pain. Its radiolabelling was developed via a four-step radiosynthesis starting from [ 11 C]CO 2 and Grignard reagent 2 . [ 11 C]Oxaprozine ( 3 ) was prepared and selectively reduced to yield aldehyde 4 , which was converted to the oxime 6 . The [ 11 C]SZV 1287 was ...
Source: ChemMedChem - September 15, 2020 Category: Chemistry Authors: Forgács V, Németh E, Gyuricza B, Kis A, Szabó JP, Mikecz P, Mátyus P, Helyes Z, Horváth ÁI, Kálai T, Trencsényi G, Fekete A, Szikra D Tags: ChemMedChem Source Type: research

The quest for the best dual orexin receptor antagonist (daridorexant) for the treatment of insomnia disorders.
We describe our efforts leading to the identification of a promising set of dual orexin receptor antagonists (DORAs) which subsequently went through physiology-based pharmacokinetic and pharmacodynamic modelling 1 and finally led to the selection of daridorexant ( 93 ) currently in phase 3 clinical trials for the treatment of insomnia disorders. PMID: 32937014 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - September 15, 2020 Category: Chemistry Authors: Boss C, Gatfield J, Brotschi C, Heidmann B, Sifferlen T, von Raumer M, Schmidt G, Williams JT, Treiber A, Roch C Tags: ChemMedChem Source Type: research

SAR of novel benzamides and isoindolines, designed as SARS-CoV protease inhibitors - effective against SARS-CoV-2.
ister T Abstract Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the non-covalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (2b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. ...
Source: ChemMedChem - September 14, 2020 Category: Chemistry Authors: Welker A, Kersten C, Müller C, Madhugiri R, Zimmer C, Müller P, Zimmermann RA, Hammerschmidt S, Maus H, Ziebuhr J, Sotriffer C, Schirmeister T Tags: ChemMedChem Source Type: research

Predicting the antimicrobial efficacy of hydrogen bonded, self-associating amphiphiles.
Abstract Herein, we report 50 structurally related supramolecular self-associating amphiphilic (SSA) salts and related compounds. These SSAs are shown to act as antimicrobial agents, active against model Gram-positive (Methicillin-Resistant Staphylococcus aureus ) and/or Gram-negative ( Escherichia coli ) bacteria of clinical interest. Through a combination of solution state, gas phase, solid state and in silico measurements we determine 14 different physicochemical parameters for each of these 50 structurally related compounds. These parameter sets are then used to identify molecular structure - physicochemical p...
Source: ChemMedChem - September 14, 2020 Category: Chemistry Authors: Allen N, White L, Boles J, Williams G, Chu D, Ellaby R, Shepherd H, Ng K, Blackholly L, Wilson B, Mulvihill D, Hiscock J Tags: ChemMedChem Source Type: research

Structure activity studies of truncated latrunculin analogues with anti-malarial activity.
This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria. PMID: 32929894 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - September 13, 2020 Category: Chemistry Authors: Varghese S, Rahmani R, Drew DR, Beeson JG, Baum J, Smith BJ, Baell J Tags: ChemMedChem Source Type: research

Gold Nanoparticles-Decorated Metal-Organic Frameworks for Anticancer Therapy.
Abstract Confinement of Au nanoparticles (NPs) within the porous materials with few nanometers (2-3 nm) has been a well established research area in the past decades in heterogeneous catalysis mainly due to the unique behaviour of Au NPs than its bulk counterpart. In this aspect, Au NPs encapsulated within the pore volumes of metal-organic frameworks (MOFs) have been intensively explored as heterogeneous solid catalyst for wide range of reactions. In recent years, Au NPs confined within the porous MOFs along with the photosensitizer or drug has been effectively used for the treatment of tumor cells through the gen...
Source: ChemMedChem - September 13, 2020 Category: Chemistry Authors: Dhakshinamoorthy A, Navalon S, Asiri AM, Garcia H Tags: ChemMedChem Source Type: research

Further SAR on the (phenylsulfonyl)piperazine scaffold as inhibitors of the  Aedes aegypti Kir1 (AeKir) channel and larvicides.
Further SAR on the (phenylsulfonyl)piperazine scaffold as inhibitors of the Aedes aegypti Kir1 (AeKir) channel and larvicides. ChemMedChem. 2020 Sep 14;: Authors: Aretz C, Kharade SV, Chronister K, Trigueros RR, Rodriguez EM, Piermarini PM, Denton JS, Hopkins CR Abstract Zika virus (ZIKV), dengue fever (DENV) and chikungunya (CHIKV) are arboviruses that are spread to humans from the bite of an infected adult female  Aedes aegypti  mosquito. As there are no effective vaccines or therapeutics for these diseases, the primary strategy for controlling the spread of these viruses is to p...
Source: ChemMedChem - September 13, 2020 Category: Chemistry Authors: Aretz C, Kharade SV, Chronister K, Trigueros RR, Rodriguez EM, Piermarini PM, Denton JS, Hopkins CR Tags: ChemMedChem Source Type: research

Peptide-Mimicking Poly(2-oxazoline)s Displaying Potent Antimicrobial Properties.
Abstract Poly(2-oxazoline)s have excellent biocompatibility and have been used as a FDA-approved indirect food additive. The inert property of the hydrophilic poly(2-oxazoline)s suggests them as promisingsubstitution of PEG in variable applications such as resisting biofouling. Recently, Liu group reported that poly(2-oxazoline)s themselves have antimicrobial properties as synthetic mimics of host defense peptides. These studies revealed the bioactive properties of poly(2-oxazoline)s as a new class of functional peptide mimics, by mimicking host defense peptide to display potent and selective antimicrobial activit...
Source: ChemMedChem - September 13, 2020 Category: Chemistry Authors: Zhou M, Jiang W, Xie J, Zhang W, Ji Z, Zou J, Cong Z, Xiao X, Gu J, Liu R Tags: ChemMedChem Source Type: research

Selected 1,3-benzodioxine-containing chalcones as multipotent monoamine oxidase and acetylcholinesterase inhibitors.
Abstract Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3-benzodioxine-containing chalcones (CD3, CD8 and CD10), and their inhibitory activities against MAO-A, MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compound CD8 most potently inhibited MAO-B with an IC50 value of 0.026 µM, followed by CD10 and CD3 (1.54 and 1.68 µM, respectively). CD8 potently and non-selectively inhibited MAO-A (IC50 = 0.023 µM). On the other hand, CD10 and CD8 in...
Source: ChemMedChem - September 12, 2020 Category: Chemistry Authors: Jeong GS, Kaipakasseri S, Lee SR, Marraiki N, Batiha GE, Dev S, Palakkathondi A, Kavully FS, Gambacorta N, Nicolotti O, Mathew B, Kim H Tags: ChemMedChem Source Type: research

A cytochrome c-chlorotoxin hybrid protein as a possible antiglioma drug.
e;rez-Paz J Abstract Malignant gliomas are the most lethal form of primary brain tumors. Despite advances in cancer therapy, the prognosis of glioma patients has remained poor. Cytochrome c (Cytc), an endogenous heme-based protein, holds tremendous potential to treat gliomas because of its innate capacity to trigger apoptosis. To this end, a hybrid cytochrome c-chlorotoxin (Cytc-CTX) protein was biosynthesized to enable cellular uptake of the cell impenetrable Cytc using CTX transporters. A nucleotide sequence containing 1:1 Cytc and CTX was constructed and separated by a hexahistidine-tag and an enterokinase clea...
Source: ChemMedChem - September 10, 2020 Category: Chemistry Authors: Delinois LJ, Peon H, Villalobos-Santos JC, Ramirez-Paz J, Miller J, Griebenow KH, Tinoco AD, Peón H, Ramírez-Paz J Tags: ChemMedChem Source Type: research

The structure of Gd(III) chelates conjugated at the periphery of 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH) make significant impact in imaging and therapy of cancer.
Abstract 3-(1'-Hexyloxyethyl)-3-devinyl-pyropheophorbide-a (HPPH or Photochlor), a tumor-avid chlorophyll-a derivative currently undergoing human clinical trials, was conjugated at different peripheral positions (position-17 or 20) of the macrocycle with either Gd(III)-aminobenzyl-DTPA ( Gd(III) DTPA ) or Gd(III)-aminoethylamido-DOTA ( Gd(III)DOTA ) moiety. The corresponding conjugates were evaluated for in vitro uptake and PDT efficacy in Colon26 tumor cell line. The T1, T2 relaxivity, in vivo fluorescence and MR imaging under similar treatment parameters were performed in BALB/c mice bearing Colon26 tumors. Amon...
Source: ChemMedChem - September 10, 2020 Category: Chemistry Authors: Zhang S, Cheruku R, Dukh M, Tabaczynski W, Patel N, White W, Missert JR, Spernyak JA, Pandey RK Tags: ChemMedChem Source Type: research

The Quest for Orally Bioavailable Selective Estrogen Receptor Degraders (SERDs).
Abstract Estrogen receptor-alpha (ERα) is the target of endocrine therapies for the treatment of more than 70% of ER α -positive breast cancers. Selective Estrogen Receptor Degraders (SERDs) antagonize estrogen binding and target the receptor for degradation, representing the last line of treatment for resistant metastatic breast cancer patients. However, the clinical efficacy of the lone clinically approved SERD (Fulvestrant) is limited by its poor oral bioavailability. Recently, several analogs of GW5638, an acrylic acid-based ER α  ligand developed by Glaxo SmithKline in 1994, have been r...
Source: ChemMedChem - September 10, 2020 Category: Chemistry Authors: Sharma A, Wang L Tags: ChemMedChem Source Type: research

Pyrrolo[1,2-a]quinoxalines: Insulin Mimetics that Exhibit Potent and Selective Inhibition against Protein Tyrosine Phosphatase 1B.
aquero JJ, Rodríguez-Puyol D Abstract PTP1B dephosphorylates insulin receptor and substrates to modulate glucose metabolism. This enzyme is a validated therapeutic target for type 2 diabetes, but no current drug candidates have completed clinical trials. Pyrrolo[1,2-a]quinoxalines substituted at positions C1-C4 and/or C7-C8 were found to be nontoxic to cells and good inhibitors in the low- to sub-micromolar range, with the 4-benzyl derivative being the most potent inhibitor (0.24 μm). Some analogues bearing chlorine atoms at C7 and/or C8 kept potency and showed good selectivity compared to TCPTP (selec...
Source: ChemMedChem - September 9, 2020 Category: Chemistry Authors: García-Marín J, Griera M, Sánchez-Alonso P, Di Geronimo B, Mendicuti F, Rodríguez-Puyol M, Alajarín R, de Pascual-Teresa B, Vaquero JJ, Rodríguez-Puyol D Tags: ChemMedChem Source Type: research

sp3 -Rich Glycyrrhetinic Acid Analogues Using Late-Stage Functionalization as Potential Breast Tumor Regressing Agents.
Abstract Late-stage functionalization (LSF) aids drug discovery efforts by introducing functional groups onto C-H bonds on pre-existing skeletons. We adopted the LSF strategy to synthesize analogues of the abundantly available triterpenoid, glycyrrhetinic acid (GA), by introducing aryl groups in the A-ring, expanding the A-ring and selectively activating one methyl group of the gem-dimethyl groups. Intriguingly, two compounds were found to preferentially accumulate in the mitochondrial compartment of MDA-MB-231 breast cancer cells, to cause depolarization of mitochondrial membrane potential and to induce antiproli...
Source: ChemMedChem - September 6, 2020 Category: Chemistry Authors: Kallepu S, Neeli PK, Mallappa S, Nagendla NK, Reddy Mudiam MK, Mainkar PS, Kotamraju S, Chandrasekhar S Tags: ChemMedChem Source Type: research

The Effects of the Alkaloid Tambjamine J on Mice Implanted with Sarcoma 180 Tumor Cells.
Abstract The tambjamines are a small group of bipyrrolic alkaloids that, collectively, display a significant range of biological activities including antitumor, antimicrobial and immunosuppressive properties. The key objective of the present study was to undertake preclinical assessments of tambjamine J (T-J) so as to determine its in vivo antitumor effects. To that end, sarcoma 180 cells were transplanted in mice and the impacts of the title compound then evaluated using a range of protocols including hematological, biochemical, histopathological, genotoxic and clastogenic assays. As a result it was established t...
Source: ChemMedChem - September 3, 2020 Category: Chemistry Authors: Banwell M, Barros-Nepomuceno FW, Viana DA, Pinheiro DP, Oliveira FCE, Ferreira JM, de Queiroz MGR, Ma X, Cavalcanti BC, Pessoa C Tags: ChemMedChem Source Type: research