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Bioorganic & Medicinal Chemistry

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https://www.readbyqxmd.com/read/28728897/1-3-oxazole-based-selective-picomolar-inhibitors-of-cytosolic-human-carbonic-anhydrase-ii-alleviate-ocular-hypertension-in-rabbits-potency-is-supported-by-x-ray-crystallography-of-two-leads
#1
Marta Ferraroni, Laura Luccarini, Emanuela Masini, Mikhail Korsakov, Andrea Scozzafava, Claudiu T Supuran, Mikhail Krasavin
Two lead 1,3-oxazole-based carbonic anhydrase inhibitors (CAIs) earlier identified as selective, picomolar inhibitors of hCA II (a cytosolic target for treatment of glaucoma) have been investigated further. Firstly, they were found to be conveniently synthesized on multigram scale, which enables further development. These compounds were found to be comparable in efficacy to dorzolamide eye drops when applied in the eye drop form as well. Finally, the reasons for unusually high potency of these compounds became understood from their high-resolution X-ray crystallography structures...
July 11, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28720326/piperidine-and-octahydropyrano-3-4-c-pyridine-scaffolds-for-drug-like-molecular-libraries-of-the-european-lead-factory
#2
Bharat D Narhe, Arjen C Breman, Jalindar Padwal, Dirk A L Vandenput, Joeri M Scheidt, Jorg C J Benningshof, Gijsbert A van der Marel, Herman S Overkleeft, Mario van der Stelt, Dmitri V Filippov
We report short and efficient scalable syntheses of enantiomerically pure (3R,4S)-3-(hydroxymethyl4-(hydroxyethyl))-piperidine and 1-hydroxymethyl-octahydro-1H-pyrano[3,4-c]pyridine scaffolds. The alkaloid core was readily synthesized from naturally occurring quinine and can serve as a valued starting point for drug-discovery. Cleavage of a terminal 1,2-diol and acid catalysed epoxide opening cyclization are the key steps involved. A number of members of a projected small-molecular library is synthesized for each scaffold...
July 10, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28728899/machine-learning-enabled-discovery-and-design-of-membrane-active-peptides
#3
Ernest Y Lee, Gerard C L Wong, Andrew L Ferguson
Antimicrobial peptides are a class of membrane-active peptides that form a critical component of innate host immunity and possess a diversity of sequence and structure. Machine learning approaches have been profitably employed to efficiently screen sequence space and guide experiment towards promising candidates with high putative activity. In this mini-review, we provide an introduction to antimicrobial peptides and summarize recent advances in machine learning-enabled antimicrobial peptide discovery and design with a focus on a recent work Lee et al...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28728896/platinum-iv-complexes-conjugated-with-phenstatin-analogue-as-inhibitors-of-microtubule-polymerization-and-reverser-of-multidrug-resistance
#4
Xiaochao Huang, Rizhen Huang, Shaohua Gou, Zhimei Wang, Zhixin Liao, Hengshan Wang
Pt(IV) complexes comprising a phenstatin analogue, as dual-targeting Pt(IV) prodrug, were designed and synthesized. They were found not only to carry the DNA binding platinum warhead into the tumor cells, but also to have a small molecular unit to inhibit tubulin polymerization. In vitro evaluation results revealed that Pt(IV) complexes showed better and more potent activity against the test human cancer cells including cisplatin resistant cell lines than their corresponding Pt(II) counterparts. In addition, the Pt(IV) derivative of cisplatin, complex 10, exhibited highly selective inhibition in human cancer cells and displayed no obvious toxicity to two human normal cell lines, respectively...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28720332/synthesis-and-biological-evaluation-of-fluoro-substituted-3-4-dihydroquinazoline-derivatives-for-cytotoxic-and-analgesic-effects
#5
Jin Han Kim, Hui Rak Jeong, Da Woon Jung, Hong Bin Yoon, Sun Young Kim, Hyoung Ja Kim, Kyung-Tae Lee, Vinicius M Gadotti, Junting Huang, Fang-Xiong Zhang, Gerald W Zamponi, Jae Yeol Lee
As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Cav3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav3.2 currents (>90% inhibition) at 10μM concentration and exhibited cytotoxic effect (IC50=5.9μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28720330/generation-of-hazardous-methyl-azide-and-its-application-to-synthesis-of-a-key-intermediate-of-picarbutrazox-a-new-potent-pesticide-in-flow
#6
Daisuke Ichinari, Aiichiro Nagaki, Jun-Ichi Yoshida
Generation and reactions of methyl azide (MeN3) were successfully performed by using a flow reactor system, demonstrating that the flow method serves as a safe method for handling hazardous explosive methyl azide. The reaction of NaN3 and Me2SO4 in a flow reactor gave a MeN3 solution, which was used for Huisgen reaction with benzoyl cyanide in a flow reactor after minimal washing. The resulting 1-methyl-5-benzoyltetrazole serves as a key intermediate of picarbutrazox (IX), a new potent pesticide.
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28720328/design-synthesis-molecular-modeling-and-anti-hyperglycemic-evaluation-of-quinazolin-4-3h-one-derivatives-as-potential-ppar%C3%AE-and-sur-agonists
#7
Mohamed K Ibrahim, Ibrahim H Eissa, Mohamed S Alesawy, Ahmed M Metwaly, Mohamed M Radwan, Mahmoud A ElSohly
Peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARγ and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19a, 19d, 19f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28720324/synthesis-and-diabetic-neuropathic-pain-alleviating-effects-of-2n-pyrazol-3-yl-methylbenzo-d-isothiazole-1-1-dioxide-derivatives
#8
Jin Ri Hong, Young Jin Choi, Gyochang Keum, Ghilsoo Nam
A novel series of fused-benzensulfonamide 2-N-(pyrazol-3-yl)methylbenzo[d]isothiazole-1,1-dioxide derivatives was designed and synthesized as metabolically stable T-type calcium channel inhibitors. Several compounds, 9, 10, and 17, displayed potent T-type channel inhibitory activity. Among them, compounds 10 and 17 showed good metabolic stability in human liver microsomes, and low hERG channel and CYP450 inhibition. Compound 10 exhibited diabetic neuropathic pain-alleviating effects in a streptozotocin-induced peripheral diabetic neuropathy (PDN) model...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28716641/synthesis-and-evaluation-of-osimertinib-derivatives-as-potent-egfr-inhibitors
#9
Hongying Gao, Zimo Yang, Xinglin Yang, Yu Rao
Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28720331/a-novel-antihypertension-agent-sargachromenol-d-from-marine-brown-algae-sargassum-siliquastrum-exerts-dual-action-as-an-l-type-ca-2-channel-blocker-and-endothelin-a-b2-receptor-antagonist
#10
Byong-Gon Park, Woon-Seob Shin, Sangtae Oh, Gab-Man Park, Nam Ik Kim, Seokjoon Lee
We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK(+))-induced basilar artery contraction with EC50 values of 3.52±0.42 and 1.62±0.63μM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50=9...
July 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28712845/dual-inhibitors-of-the-human-blood-brain-barrier-drug-efflux-transporters-p-glycoprotein-and-abcg2-based-on-the-antiviral-azidothymidine
#11
Hilda A Namanja-Magliano, Kelsey Bohn, Neha Agrawal, Meghan E Willoughby, Christine A Hrycyna, Jean Chmielewski
The brain provides a sanctuary site for HIV due, in part, to poor penetration of antiretroviral agents at the blood-brain barrier. This lack of penetration is partially attributed to drug efflux transporters such as P-glycoprotein (P-gp) and ABCG2. Inhibition of both ABCG2 and P-gp is critical for enhancing drug accumulation into the brain. In this work, we have developed a class of homodimers based on the HIV reverse transcriptase inhibitor azidothymidine (AZT) that effectively inhibits P-gp and ABCG2. These agents block transporter mediated efflux of the P-gp substrate calcein-AM and the ABCG2 substrate mitoxantrone...
July 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28728898/kbe009-an-antimalarial-bestatin-like-inhibitor-of-the-plasmodium-falciparum-m1-aminopeptidase-discovered-in-an-ugi-multicomponent-reaction-derived-peptidomimetic-library
#12
Jorge González-Bacerio, Sarah El Chamy Maluf, Yanira Méndez, Isel Pascual, Isabelle Florent, Pollyana M S Melo, Alexandre Budu, Juliana C Ferreira, Ernesto Moreno, Adriana K Carmona, Daniel G Rivera, Maday Alonso Del Rivero, Marcos L Gazarini
Malaria is a global human parasitic disease mainly caused by the protozoon Plasmodium falciparum. Increased parasite resistance to current drugs determines the relevance of finding new treatments against new targets. A novel target is the M1 alanyl-aminopeptidase from P. falciparum (PfA-M1), which is essential for parasite development in human erythrocytes and is inhibited by the pseudo-peptide bestatin. In this work, we used a combinatorial multicomponent approach to produce a library of peptidomimetics and screened it for the inhibition of recombinant PfA-M1 (rPfA-M1) and the in vitro growth of P...
July 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28720329/recent-synthetic-and-medicinal-perspectives-of-tryptanthrin
#13
REVIEW
Ramandeep Kaur, Sundeep Kaur Manjal, Ravindra K Rawal, Kapil Kumar
Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A-C, pyrroloindoloquinazoline, (±)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial...
July 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28720325/therapeutic-peptides-historical-perspectives-current-development-trends-and-future-directions
#14
Jolene L Lau, Michael K Dunn
Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States and other major markets, and peptides continue to enter clinical development at a steady pace. Peptide drug discovery has diversified beyond its traditional focus on endogenous human peptides to include a broader range of structures identified from other natural sources or through medicinal chemistry efforts. We maintain a comprehensive dataset on peptides that have entered human clinical studies that includes over 150 peptides in active development today...
July 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28698054/bistacrines-as-potential-antitrypanosomal-agents
#15
Ines Schmidt, Sarah Göllner, Antje Fuß, August Stich, Anna Kucharski, Tanja Schirmeister, Elena Katzowitsch, Heike Bruhn, Alexandra Miliu, R Luise Krauth-Siegel, Ulrike Holzgrabe
Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with IC50-values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity...
July 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28705434/nanoparticle-macrophage-interactions-a-balance-between-clearance-and-cell-specific-targeting
#16
Rahul Rattan, Somnath Bhattacharjee, Hong Zong, Corban Swain, Muneeb A Siddiqui, Scott H Visovatti, Yogendra Kanthi, Sajani Desai, David J Pinsky, Sascha N Goonewardena
The surface properties of nanoparticles (NPs) are a major factor that influences how these nanomaterials interact with biological systems. Interactions between NPs and macrophages of the reticuloendothelial system (RES) can reduce the efficacy of NP diagnostics and therapeutics. Traditionally, to limit NP clearance by the RES system, the NP surface is neutralized with molecules like poly(ethylene glycol) (PEG) which are known to resist protein adsorption and RES clearance. Unfortunately, PEG modification is not without drawbacks including difficulties with the synthesis and associations with immune reactions...
June 30, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28720327/asymmetric-synthesis-and-evaluation-of-epoxy-%C3%AE-acyloxycarboxamides-as-selective-inhibitors-of-cathepsin-l
#17
Deborah A Dos Santos, Anna Maria Deobald, Vivian E Cornelio, Roberta M D Ávila, Renata C Cornea, Gilberto C R Bernasconi, Marcio W Paixão, Paulo C Vieira, Arlene G Corrêa
Cathepsin L plays important roles in physiological processes as well as in the development of many pathologies. Recently the attentions were turned to its association with tumor progress what makes essential the development of more potent and selective inhibitors. In this work, epoxipeptidomimetics were investigated as new cathepsin inhibitors. This class of compounds is straightforward obtained by using a green one-pot asymmetric epoxidation/Passerini 3-MCR. A small library of 17 compounds was evaluated against cathepsin L, and among them LSPN423 showed to be the most potent...
June 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28689977/design-and-synthesis-of-potent-and-orally-active-gpr4-antagonists-with-modulatory-effects-on-nociception-inflammation-and-angiogenesis
#18
Wolfgang Miltz, Juraj Velcicky, Janet Dawson, Amanda Littlewood-Evans, Marie-Gabrielle Ludwig, Klaus Seuwen, Roland Feifel, Berndt Oberhauser, Arndt Meyer, Daniela Gabriel, Mark Nash, Pius Loetscher
GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain.
June 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28689975/the-medicinal-chemistry-of-chikungunya-virus
#19
REVIEW
Edeildo F da Silva-Júnior, Giovanni O Leoncini, Érica E S Rodrigues, Thiago M Aquino, João X Araújo-Júnior
Arthropod-borne viruses (arboviruses) are an important threat to human and animal health globally. Among these, zoonotic diseases account for billions of cases of human illness and millions of deaths every year, representing an increasing public health problem. Chikungunya virus belongs to the genus Alphavirus of the family Togariridae, and is transmitted mainly by the bite of female mosquitoes of the Aedes aegypti and/or A. albopictus species. The focus of this review will be on the medicinal chemistry of Chikungunya virus, including synthetic and natural products, as well as rationally designed compounds...
June 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28716640/complex-molecules-clever-solutions-enzymatic-approaches-towards-natural-product-and-active-agent-syntheses
#20
REVIEW
Thomas Classen, Jörg Pietruszka
Natural compounds are often structurally complex and their synthesis is still highly challenging. The review intends to give an overview on developments in biotechnology and their role for the production of natural products and active agents. In vitro and in vivo methods are presented side by side beginning with rather simple but smart single step conversions, followed by cascade reactions, and finishing with complex bio-, semi- and mutasynthesis endeavours. All the enzymatic approaches do obviously complement traditional synthetic methods; with their particular strengths, the combined repertoire will lead to an increased efficiency in natural product synthesis as well as in providing analogues...
June 28, 2017: Bioorganic & Medicinal Chemistry
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