Identification of a new class of HBV capsid assembly modulator
Bioorg Med Chem Lett. 2021 Feb 18:127848. doi: 10.1016/j.bmcl.2021.127848. Online ahead of print.ABSTRACTThe HBV core protein is a druggable target of interest due to the multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly has shown efficacy in clinical trials. Herein is described the identification and hit to lead SAR of a novel series of pyrazolo piperidine HBV capsid assembly modulators.PMID:33610748 | DOI:10.1016/j.bmcl.2021.127848 (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - February 21, 2021 Category: Chemistry Authors: Scott D Kuduk Bart Stoops Richard Alexander Angela M Lam Christine Espiritu Robert Vogel Vincent Lau Klaus Klumpp Osvaldo A Flores George D Hartman Source Type: research

Design, synthesis and biological evaluation of mono- and bisquinoline methanamine derivatives as potential antiplasmodial agents
Bioorg Med Chem Lett. 2021 Feb 17:127855. doi: 10.1016/j.bmcl.2021.127855. Online ahead of print.ABSTRACTSeveral classes of antimalarial drugs are currently available, although issues of toxicity and the emergence of drug resistant malaria parasites have reduced their overall therapeutic efficiency. Quinoline based antiplasmodial drugs have unequivocally been long-established and continue to inspire the design of new antimalarial agents. Herein, a series of mono- and bisquinoline methanamine derivatives were synthesised through sequential steps; Vilsmeier-Haack, reductive amination, and nucleophilic substitution, and obtai...
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2021 Category: Chemistry Authors: Fostino R B Bokosi Richard M Beteck Mziyanda Mbaba Thanduxolo E Mtshare Dustin Laming Heinrich C Hoppe Setshaba D Khanye Source Type: research

Pyridones in drug discovery: recent advances
Bioorg Med Chem Lett. 2021 Feb 17:127849. doi: 10.1016/j.bmcl.2021.127849. Online ahead of print.ABSTRACTPyridones have been utilized as privileged scaffolds in drug discovery. Some of the important roles where this class of heterocycles have found utility in medicinal chemistry include the ability to 1) serve both as a hydrogen bond acceptor and/or a donor; 2) act as a bioisostere for amides, phenyls, pyridines and other nitrogen- or oxygen-containing heterocycles; and 3) impact a target drug molecule's lipophilicity, aqueous solubility and metabolic stability. Detailed discussions of recent advances in their utilization ...
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2021 Category: Chemistry Authors: Yun Zhang Andrew Pike Source Type: research

Design, synthesis and bioactivity evaluation of novel pyrazole linked phenylthiazole derivatives in context of antibacterial activity
This study presents a structure-activity relationship (SAR) rationale for pyrazole linked phenylthiazole analogues as new antibacterial agents. A library of 23 novel pyrazole linked phenylthiazole compounds were synthesised, followed by screening for antimicrobial activity against five bacterial species and two fungi. The most active compound 14b has shown promising antibacterial activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) strain (MIC 4 μg/mL). Furthermore, the active pyrazole linked phenylthiazole compound exhibited a better toxicity profile than standard antibiotic...
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2021 Category: Chemistry Authors: Bhautikkumar Patel Matthew Zunk Gary Grant Santosh Rudrawar Source Type: research

Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva
Bioorg Med Chem Lett. 2021 Feb 17:127858. doi: 10.1016/j.bmcl.2021.127858. Online ahead of print.ABSTRACTMutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 effi...
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2021 Category: Chemistry Authors: Hirofumi Yamamoto Naoki Sakai Satoshi Ohte Tomohiro Sato Katsuhiko Sekimata Takehisa Matsumoto Kana Nakamura Hisami Watanabe Chiemi Mishima-Tsumagari Akiko Tanaka Yoshinobu Hashizume Teruki Honma Takenobu Katagiri Kohei Miyazono Hiroshi Tomoda Mikako Shir Source Type: research

Small molecule approaches to treat autoimmune and inflammatory diseases (Part I): kinase inhibitors
Bioorg Med Chem Lett. 2021 Feb 17:127862. doi: 10.1016/j.bmcl.2021.127862. Online ahead of print.ABSTRACTAutoimmune and inflammatory diseases place a huge burden on the healthcare system. Small molecule (SM) therapeutics provide much needed complementary treatment options for these diseases. This digest series highlights the latest progress in the discovery and development of safe and efficacious SMs to treat autoimmune and inflammatory diseases with each part representing a class of SMs, namely: 1) protein kinases; 2) nucleic acid-sensing pathways; and 3) soluble ligands and receptors on cell surfaces. In this first part ...
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2021 Category: Chemistry Authors: Jiamin Zheng Jun Wu Xiao Ding Hong C Shen Ge Zou Source Type: research

Machine learning classifiers aid virtual screening for efficient design of mini-protein therapeutics
In this study we trained machine learning classifiers which can distinguish, with 90% accuracy and 80% precision, mini-protein binders from non-binding molecules designed for a particular target; this significantly reduces the number of mini protein candidates for experimental screening. Further, on the basis of our results we propose a multi-stage protocol where a small dataset (few hundred experimentally verified target-specific mini-proteins) can be used to train classifiers for improving the efficiency of mini-protein design for any specific target.PMID:33609660 | DOI:10.1016/j.bmcl.2021.127852 (Source: Bioorganic and ...
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2021 Category: Chemistry Authors: Neeraj K Gaur Venuka Durani Goyal Kiran Kulkarni Ravindra D Makde Source Type: research

Discovery of novel Hsp90 C-terminal domain inhibitors that disrupt co-chaperone binding
Bioorg Med Chem Lett. 2021 Feb 17:127857. doi: 10.1016/j.bmcl.2021.127857. Online ahead of print.ABSTRACTHeat shock protein 90 (Hsp90) is an essential molecular chaperone that performs vital stress-related and housekeeping functions in cells and is a current therapeutic target for diseases such as cancers. Particularly, the development of Hsp90 C-terminal domain (CTD) inhibitors is highly desirable as inhibitors that target the N-terminal nucleotide-binding domain may cause unwanted biological effects. Herein, we report on the discovery of two drug-like novel Hsp90 CTD inhibitors by using virtual screening and intrinsic pr...
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2021 Category: Chemistry Authors: Oi Wei Mak Nabangshu Sharma J óhannes Reynisson Ivanhoe K H Leung Source Type: research

Prenylated flavonoids from Ficus hirta induces HeLa cells apoptosis via MAPK and AKT signaling pathways
Bioorg Med Chem Lett. 2021 Feb 17:127859. doi: 10.1016/j.bmcl.2021.127859. Online ahead of print.ABSTRACTA pair of undescribed enantiomers, (±) ficusflavonid A (1a/1b), along with five known analogues, were isolated from the roots of Ficus hirta. Their structures were determined by the analysis of extensive spectroscopic data (including UV, IR, HRESIMS and NMR). Two enantiomers (1a and 1b) were successfully separated by chiral chromatographic column and their absolute configurations were assigned by the comparison of experimental and calculated ECD data. The cytotoxicity of all the isolates against HeLa, MCF-7, HepG...
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2021 Category: Chemistry Authors: Xian-Sheng Ye Wen-Jing Tian Mi Zhou De-Quan Zeng Ting Lin Guang-Hui Wang Xin-Sheng Yao Hai-Feng Chen Source Type: research

3-Functionalised Benzenesulphonamide based 1,3,4-oxadiazoles as Selective Carbonic Anhydrase XIII Inhibitors: Design, Synthesis and Biological Evaluation
Bioorg Med Chem Lett. 2021 Feb 17:127856. doi: 10.1016/j.bmcl.2021.127856. Online ahead of print.ABSTRACTA new series of benzenesulphonamide linked-1,3,4-oxadiazole hybrids (6a-s) has been synthesized and tested for their carbonic anhydrase inhibition against human (h) carbonic anhydrase (CA) isoforms hCA I, II, IX, and XIII. Fluorescence properties of some of the synthesised molecules were studied. Most of the molecules exhibited significant inhibitory power, comparable or better than the standard drug acetazolamide (AAZ) on hCA XIII. Out of 19 tested molecules, compound 6e (75.8 nM) was 3 times more potent than AAZ (250....
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2021 Category: Chemistry Authors: Baijayantimala Swain None Abhay Priti Singh Andrea Angeli Kamtam Aashritha Narayana Nagesh Claudiu T Supuran Mohammed Arifuddin Source Type: research

Design, synthesis and biological evaluation of mono- and bisquinoline methanamine derivatives as potential antiplasmodial agents.
Abstract Several classes of antimalarial drugs are currently available, although issues of toxicity and the emergence of drug resistant malaria parasites have reduced their overall therapeutic efficiency. Quinoline based antiplasmodial drugs have unequivocally been long-established and continue to inspire the design of new antimalarial agents. Herein, a series of mono- and bisquinoline methanamine derivatives were synthesised through sequential steps; Vilsmeier-Haack, reductive amination, and nucleophilic substitution, and obtained in low to excellent yields. The resulting compounds were investigated for in vitro ...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2021 Category: Chemistry Authors: Bokosi FRB, Beteck RM, Mbaba M, Mtshare TE, Laming D, Hoppe HC, Khanye SD Tags: Bioorg Med Chem Lett Source Type: research

Pyridones in drug discovery: recent advances.
Abstract Pyridones have been utilized as privileged scaffolds in drug discovery. Some of the important roles where this class of heterocycles have found utility in medicinal chemistry include the ability to 1) serve both as a hydrogen bond acceptor and/or a donor; 2) act as a bioisostere for amides, phenyls, pyridines and other nitrogen- or oxygen-containing heterocycles; and 3) impact a target drug molecule's lipophilicity, aqueous solubility and metabolic stability. Detailed discussions of recent advances in their utilization as nonpeptidic mimics and as kinase hinge binding motifs are included. Selected literat...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2021 Category: Chemistry Authors: Zhang Y, Pike A Tags: Bioorg Med Chem Lett Source Type: research

Design, synthesis and bioactivity evaluation of novel pyrazole linked phenylthiazole derivatives in context of antibacterial activity.
This study presents a structure-activity relationship (SAR) rationale for pyrazole linked phenylthiazole analogues as new antibacterial agents. A library of 23 novel pyrazole linked phenylthiazole compounds were synthesised, followed by screening for antimicrobial activity against five bacterial species and two fungi. The most active compound 14b has shown promising antibacterial activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) strain (MIC 4 μg/mL). Furthermore, the active pyrazole linked phenylthiazole compound exhibited a better toxicity profile than standard antibiotic...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2021 Category: Chemistry Authors: Patel B, Zunk M, Grant G, Rudrawar S Tags: Bioorg Med Chem Lett Source Type: research

Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva.
Abstract Mutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase act...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2021 Category: Chemistry Authors: Yamamoto H, Sakai N, Ohte S, Sato T, Sekimata K, Matsumoto T, Nakamura K, Watanabe H, Mishima-Tsumagari C, Tanaka A, Hashizume Y, Honma T, Katagiri T, Miyazono K, Tomoda H, Shirouzu M, Koyama H Tags: Bioorg Med Chem Lett Source Type: research

Small molecule approaches to treat autoimmune and inflammatory diseases (Part I): kinase inhibitors.
Abstract Autoimmune and inflammatory diseases place a huge burden on the healthcare system. Small molecule (SM) therapeutics provide much needed complementary treatment options for these diseases. This digest series highlights the latest progress in the discovery and development of safe and efficacious SMs to treat autoimmune and inflammatory diseases with each part representing a class of SMs, namely: 1) protein kinases; 2) nucleic acid-sensing pathways; and 3) soluble ligands and receptors on cell surfaces. In this first part of the series, the focus is on kinase inhibitors that emerged between 2018 and 2020, an...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2021 Category: Chemistry Authors: Zheng J, Wu J, Ding X, Shen HC, Zou G Tags: Bioorg Med Chem Lett Source Type: research

Machine learning classifiers aid virtual screening for efficient design of mini-protein therapeutics.
In this study we trained machine learning classifiers which can distinguish, with 90% accuracy and 80% precision, mini-protein binders from non-binding molecules designed for a particular target; this significantly reduces the number of mini protein candidates for experimental screening. Further, on the basis of our results we propose a multi-stage protocol where a small dataset (few hundred experimentally verified target-specific mini-proteins) can be used to train classifiers for improving the efficiency of mini-protein design for any specific target. PMID: 33609660 [PubMed - as supplied by publisher] (Source: Bioor...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2021 Category: Chemistry Authors: Gaur NK, Goyal VD, Kulkarni K, Makde RD Tags: Bioorg Med Chem Lett Source Type: research

Discovery of novel Hsp90 C-terminal domain inhibitors that disrupt co-chaperone binding.
Abstract Heat shock protein 90 (Hsp90) is an essential molecular chaperone that performs vital stress-related and housekeeping functions in cells and is a current therapeutic target for diseases such as cancers. Particularly, the development of Hsp90 C-terminal domain (CTD) inhibitors is highly desirable as inhibitors that target the N-terminal nucleotide-binding domain may cause unwanted biological effects. Herein, we report on the discovery of two drug-like novel Hsp90 CTD inhibitors by using virtual screening and intrinsic protein fluorescence quenching binding assays, paving the way for future development of n...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2021 Category: Chemistry Authors: Mak OW, Sharma N, Reynisson J, Leung IKH Tags: Bioorg Med Chem Lett Source Type: research

Prenylated flavonoids from Ficus hirta induces HeLa cells apoptosis via MAPK and AKT signaling pathways.
Abstract A pair of undescribed enantiomers, (±) ficusflavonid A (1a/1b), along with five known analogues, were isolated from the roots of Ficus hirta. Their structures were determined by the analysis of extensive spectroscopic data (including UV, IR, HRESIMS and NMR). Two enantiomers (1a and 1b) were successfully separated by chiral chromatographic column and their absolute configurations were assigned by the comparison of experimental and calculated ECD data. The cytotoxicity of all the isolates against HeLa, MCF-7, HepG2 and H460 cell lines were evaluated by MTT assay. Among them, 4 suppressed the prolife...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2021 Category: Chemistry Authors: Ye XS, Tian WJ, Zhou M, Zeng DQ, Lin T, Wang GH, Yao XS, Chen HF Tags: Bioorg Med Chem Lett Source Type: research

3-Functionalised Benzenesulphonamide based 1,3,4-oxadiazoles as Selective Carbonic Anhydrase XIII Inhibitors: Design, Synthesis and Biological Evaluation.
Abstract A new series of benzenesulphonamide linked-1,3,4-oxadiazole hybrids (6a-s) has been synthesized and tested for their carbonic anhydrase inhibition against human (h) carbonic anhydrase (CA) isoforms hCA I, II, IX, and XIII. Fluorescence properties of some of the synthesised molecules were studied. Most of the molecules exhibited significant inhibitory power, comparable or better than the standard drug acetazolamide (AAZ) on hCA XIII. Out of 19 tested molecules, compound 6e (75.8 nM) was 3 times more potent than AAZ (250.0 nM) against hCA I, whereas compound 6e (15.4 nM), 6g (16.2 nM), 6h (16.4 nM) and 6i (...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2021 Category: Chemistry Authors: Swain B, Abhay, Singh P, Angeli A, Aashritha K, Nagesh N, Supuran CT, Arifuddin M Tags: Bioorg Med Chem Lett Source Type: research

Corrigendum to "Structure guided development of potent piperazine-derived hydroxamic acid inhibitors targeting falcilysin" [Bioorg. Med. Chem. Lett. 32 (2021) 127683].
Corrigendum to "Structure guided development of potent piperazine-derived hydroxamic acid inhibitors targeting falcilysin" [Bioorg. Med. Chem. Lett. 32 (2021) 127683]. Bioorg Med Chem Lett. 2021 Feb 13;37:127836 Authors: Kahlon G, Lira R, Masvlov N, Pompa E, Brar N, Eagon S, Anderson MO, Andaya A, Chance JP, Fejzic H, Keniston A, Huynh N, Celis N, Vidal B, Trieu N, Rodriguez P, Mallari JP PMID: 33588181 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - February 13, 2021 Category: Chemistry Authors: Kahlon G, Lira R, Masvlov N, Pompa E, Brar N, Eagon S, Anderson MO, Andaya A, Chance JP, Fejzic H, Keniston A, Huynh N, Celis N, Vidal B, Trieu N, Rodriguez P, Mallari JP Tags: Bioorg Med Chem Lett Source Type: research

Synthesis of polyenylpyrrole derivatives with selective growth inhibitory activity against T-cell acute lymphoblastic leukemia cells.
Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a hardly curable disease with a high relapse rate. 20 analogs were synthesized based on the structures of two kinds of fungi-derived polyenylpyrrole products (rumbrin (1) and auxarconjugatin-B (2)) to suppress the growth of T-ALL-derived cell line CCRF-CEM and tested for growth-inhibiting activity. The octatetraenylpyrrole analog gave an IC50 of 0.27 μM in CCRF-CEM cells, while it did not affect Burkitt lymphoma-derived cell line Raji and the cervical cancer cell line HeLa, or the oral cancer cell line HSC-3 (IC50> 10 μM). This compound will be a pro...
Source: Bioorganic and Medicinal Chemistry Letters - February 10, 2021 Category: Chemistry Authors: Yoshida C, Higashi T, Hachiro Y, Fujita Y, Yagi T, Takechi A, Nakata C, Miyashita K, Kitada N, Saito R, Obata R, Hirano T, Hara T, Maki SA Tags: Bioorg Med Chem Lett Source Type: research

Structure, solubility, and permeability relationships in a diverse middle molecule library.
Abstract To develop methodology to predict the potential druggability of middle molecules, we examined the structure, solubility, and permeability relationships of a diverse library (HKDL ver.1) consisting of 510 molecules (359 natural product derivatives, 76 non-natural products, 46 natural products, and 29 non-natural product derivatives). The library included peptides, depsipeptides, macrolides, and lignans, and 476 of the 510 compounds had a molecular weight in the range of 500 to 2,000 Da. The solubility and passive diffusion velocity of the middle molecules were assessed using the parallel artificial membran...
Source: Bioorganic and Medicinal Chemistry Letters - February 8, 2021 Category: Chemistry Authors: Miyachi H, Kanamitsu K, Ishii M, Watanabe E, Katsuyama A, Otsuguro S, Yakushiji F, Watanabe M, Matsui K, Sato Y, Shuto S, Tadokoro T, Kita S, Matsumaru T, Matsuda A, Hirose T, Iwatsuki M, Shigeta Y, Nagano T, Kojima H, Ichikawa S, Sunazuka T, Maenaka K Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and antifungal activity of polycyclic pyridone derivatives with anti-hyphal and biofilm formation activity against Candida albicans.
Abstract Thirty-five pyridone derivatives were synthesized, with derivatization conducted on polycyclic pyridone scaffolds, including cis- or trans-oxydecalin and other cyclic structures, by domino-Knoevenagel-electrocyclic reactions. The anti-fungal activities of the synthesized compounds were tested against Candida albicans. Ten compounds inhibited hyphal formation without inhibiting growth. Pyridones with anti-hyphal formation activity (4c, 6d, 12a and 12c) were tested for their ability to inhibit biofilm formation. Compound 6d showed both anti-hyphal and biofilm inhibition activity. PMID: 33571649 [PubMed...
Source: Bioorganic and Medicinal Chemistry Letters - February 8, 2021 Category: Chemistry Authors: Kamauchi H, Kimura Y, Ushiwatari M, Suzuki M, Seki T, Takao K, Sugita Y Tags: Bioorg Med Chem Lett Source Type: research

Identification of BR102910 as a selective fibroblast activation protein (FAP) inhibitor.
Abstract Fibroblast activation protein (FAP) belongs to the family of prolyl-specific serine proteases and displays both exopeptidase and endopeptidase activities. FAP expression is undetectable in most normal adult tissues, but is greatly upregulated in sites of tissue remodeling, which include fibrosis, inflammation and cancer. Due to its restricted expression pattern and dual enzymatic activities, FAP inhibition is investigated as a therapeutic option for several diseases. In the present study, we described the structure-activity relationship of several synthesized compounds against DPPIV and prolyl oligopeptid...
Source: Bioorganic and Medicinal Chemistry Letters - February 8, 2021 Category: Chemistry Authors: Jin Jung H, Hye Nam E, Young Park J, Ghosh P, Su Kim I Tags: Bioorg Med Chem Lett Source Type: research

Synthesis Of Novel Potent Cytotoxicy Podophyllotoxin-Naphthoquinone Compounds via Microwave-Assited Multicomponent Domino Reactions.
Abstract A series of novel podophyllotoxin-naphthoquinone compounds 5a-p were synthesized in good yields using microwave-assisted four-component reactions of 2-hydroxy-1,4-naphthoquinone, aromatic benzaldehydes, tetronic acid and ammonium acetate. All the synthezied compounds were fully characterized by spectral data and evaluated for their cytotoxicity activities against KB, HepG2, Lu1, MCF7, and non-cancerous Hek-293 cell lines. Among 16 new compounds screened, compounds 5a, 5d, 5h, and 5k displayed high potent inhibitory activities with IC50
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2021 Category: Chemistry Authors: Giang Nguyen Thi Q, Le-Nhat-Thuy G, Anh Dang Thi T, Hoang Thi P, Nguyen Tuan A, Ha Nguyen Thi T, Tra Nguyen T, Nguyen Ha T, Hoang Mai H, Van Nguyen T Tags: Bioorg Med Chem Lett Source Type: research

Synthesis of norisoboldine derivatives and bioactivity assay for inducing the generation of regulatory T cells.
In this study, we used chemical modification to improve the pharmacological activity of norisoboldine (NOR). A new NOR-benzoic acid derivative, named DC-01, showed more potent induction of Treg cell differentiation than NOR. The in vitro effective concentration of DC-01 (1 μM) is about an order of magnitude lower than that of NOR (10 μM). DC-01 (28, 56 mg/kg) showed better amelioration of dextran sodium sulfate-induced colitis in mice than NOR (20, 40 mg/kg), and DC-01 (28 mg/kg) increased the number of Treg cells slightly better than NOR (20 mg/kg). In summary, DC-01 exerts more potent induction of Treg cell generat...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2021 Category: Chemistry Authors: Chang L, Zhang Q, Tang Y, Fang Y, Dou R, Chu Y, Xia Y, Wei Z, Chen L, Dai Y Tags: Bioorg Med Chem Lett Source Type: research

Bioconjugated technetium carbonyls by transmetalation reaction with zinc derivatives.
des J Abstract The transmetalation reaction between zinc dithiocarbamates functionalized with organic groups and the cation fac-[99mTc(H2O)3(CO)3]+ has been studied as a new strategy to bind biomolecules to this radionuclide for preparing radiopharmaceuticals with high molar activity. All complexes were obtained in high yields by heating at moderate temperatures and without subsequent purification. The chemical identity was ascertained by HPLC comparison with the homologous rhenium complexes. Stability studies in cysteine solution and serum have shown a good stability of the coordination set fac-[99mTc(CO)3(SS)(P)...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2021 Category: Chemistry Authors: Borràs J, Lecina J, Foster J, Kashani R, Melendez-Alafort L, Sosabowski J, Suades J Tags: Bioorg Med Chem Lett Source Type: research

Design, synthesis and biological evaluation of dihydrofurocoumarin derivatives as potent neuraminidase inhibitors.
In this study a dihydrofurocoumarin derivative ZINC05577497 was discovered as a lead NA inhibitor based on docking-based virtual screening technique. The optimization of lead ZINC05577497 led to the discovery of a series of novel NA inhibitors 5a-5j. Compound 5b has the most potent activity against NA with IC50=0.02 µM, which is lower than those of the reference oseltamivir carboxylate (OSC) (IC50=0.04 µM) and ZINC05577497 (IC50=0.11 µM). Other target compounds also show potential inhibition of NA activity. Molecular docking results indicate that the good potency of 5b may be attributed to the elongation ...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2021 Category: Chemistry Authors: Jian Zhong Z, Ping Cheng L, Pang W, Song Zheng X, Kai Fu S Tags: Bioorg Med Chem Lett Source Type: research

Discovery and optimization of a novel CNS penetrant series of mGlu4 PAMs based on a 1,4-thiazepane core with in vivo efficacy in a preclinical Parkinsonian model.
Abstract A high throughput screen (HTS) identified a novel, but weak (EC50 = 6.2 μM, 97% Glu Max) mGlu4 PAM chemotype based on a 1,4-thiazepane core, VU0544412. Reaction development and chemical optimization delivered a potent mGlu4 PAM VU6022296 (EC50 = 32.8 nM, 108% Glu Max) with good CNS penetration (Kp = 0.45, Kp,uu = 0.70) and enantiopreference. Finally, VU6022296 displayed robust, dose-dependent efficacy in reversing Haloperidol-Induced Catalepsy (HIC), a rodent preclinical Parkinson's disease model. PMID: 33556572 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2021 Category: Chemistry Authors: Kent CN, Fulton MG, Stillwell KJ, Dickerson JW, Loch MT, Rodriguez AL, Blobaum AL, Boutaud O, Rook JL, Niswender CM, Jeffrey Conn P, Lindsley CW Tags: Bioorg Med Chem Lett Source Type: research

Design, synthesis, and anti-tumor activities of novel Brevinin-1BYa peptidomimetics.
In this study, a series of novel Brevinin-1BYa derivatives, including O-linked N-acetyl-glucosamine glyclopeptides and disulfide bond mimetics, were designed and synthesized. Additionally, their anti-tumor activity against human prostate cancer cell line C4-2B, human NSCLC cell line A549 (adenocarcinoma), and human hepatoma cells line HuH-7 was investigated. Among these, the thioether bridge substituted peptidomimetic Brevinin-1BYa-3 displayed improved reduction stability, more stable secondary structure, greater protease stability, and increased anti-tumor activity compared with the original peptide, rendering it a promis...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2021 Category: Chemistry Authors: Xiong S, Wang N, Liu C, Shen H, Qu Z, Zhu L, Bai X, Hu HG, Cong W, Zhao L Tags: Bioorg Med Chem Lett Source Type: research

Selection of fluorescent biosensors against galectin-3 from an NBD-modified phage library displaying designed α-helical peptides.
Selection of fluorescent biosensors against galectin-3 from an NBD-modified phage library displaying designed α-helical peptides. Bioorg Med Chem Lett. 2021 Feb 05;:127835 Authors: Hashimoto M, Miki T, Ven Chang I, Tsutsumi H, Mihara H Abstract Fluorescent biosensors are indispensable tools for molecular imaging, detection, and drug screening. Conventionally, fluorescent biosensors were constructed by incorporating fluorophores into ligands. Here, to develop ligand-independent biosensors, we demonstrated biosensor selection from a fluorophore-modified peptide phage library. In this library, the ...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2021 Category: Chemistry Authors: Hashimoto M, Miki T, Ven Chang I, Tsutsumi H, Mihara H Tags: Bioorg Med Chem Lett Source Type: research

Indolyl- α-keto-1,3,4-oxadiazoles: synthesis, anti-cell proliferation activity, and inhibition of tubulin polymerization.
Indolyl-α-keto-1,3,4-oxadiazoles: synthesis, anti-cell proliferation activity, and inhibition of tubulin polymerization. Bioorg Med Chem Lett. 2021 Feb 05;:127842 Authors: Tantak MP, Malik M, Klingler L, Olson Z, Kumar A, Sadana R, Kumar D Abstract A series of novel indolyl-α-keto-1,3,4-oxadiazole derivatives have been synthesized by employing molecular iodine-mediated oxidative cyclization of acylhydrazones. In vitro anti cell proliferation activity of these derivatives against various cancer cells lines such as human lymphoblast (U937), leukemia (Jurkat & SB) and human breast (BT474)...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2021 Category: Chemistry Authors: Tantak MP, Malik M, Klingler L, Olson Z, Kumar A, Sadana R, Kumar D Tags: Bioorg Med Chem Lett Source Type: research

Promising hit compounds against resistant trichomoniasis: synthesis and antiparasitic activity of 3-( ω-aminoalkoxy)-1-benzyl-5-nitroindazoles.
Promising hit compounds against resistant trichomoniasis: synthesis and antiparasitic activity of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles. Bioorg Med Chem Lett. 2021 Feb 05;:127843 Authors: Ibáñez-Escribano A, Reviriego F, Vela N, Fonseca-Berzal C, José Nogal-Ruiz J, Arán VJ, Antonio Escario J, Gómez-Barrio A Abstract A series of 11 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles (2-12) has been prepared starting from 1-benzyl-5-nitroindazol-3-ol 13, and evaluated against sensitive and resistant isolates of the sexually transmitted protozoan Trichomonas v...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2021 Category: Chemistry Authors: Ibáñez-Escribano A, Reviriego F, Vela N, Fonseca-Berzal C, José Nogal-Ruiz J, Arán VJ, Antonio Escario J, Gómez-Barrio A Tags: Bioorg Med Chem Lett Source Type: research

Dioxotriazine derivatives as a new class of P2X3 receptor antagonists: Identification of a lead and initial SAR studies.
Abstract P2X3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X3 receptor antagonists for the treatment of chronic pain or cough. To identify a P2X3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X3 receptors (IC50, 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selec...
Source: Bioorganic and Medicinal Chemistry Letters - February 1, 2021 Category: Chemistry Authors: Kai H, Horiguchi T, Kameyama T, Asahi K, Endoh T, Jikihara S, Hasegawa T, Tanaka S, Nozu A, Takeyama C, Tomari M, Takahashi F, Tamura N, Yagi S, Itoh T, Isou Y Tags: Bioorg Med Chem Lett Source Type: research

DNA-cleavage activity of the iron(II) complex with optically active ligands, meta- and para-xylyl-linked N',N'-dipyridylmethyl-cyclohexane-1,2-diamine.
In this study, to develop novel compounds with specific DNA-cleavage activities, we synthesized optically active binuclear ligands, (1R,1'R,2R,2'R)-N1,N1'-(meta/para-phenylenebis(methylene))bis(N2,N2-bis(pyridin-2-ylmethyl)cyclohexane-1,2-diamine) and their enantiomers. The DNA-cleavage activities of these compounds were investigated in the presence of Fe(II)SO4 and sodium ascorbate. The obtained results indicated that the Fe(II) complexes of those compounds efficiently cleave DNA and that their cleavage was subtle sequence-selective. Therefore, we succeeded in developing compounds that can be used as small-molecule drugs ...
Source: Bioorganic and Medicinal Chemistry Letters - February 1, 2021 Category: Chemistry Authors: Kato K, Ichimaru Y, Okuno Y, Yamaguchi Y, Jin W, Fujita M, Otsuka M, Imai M, Kurosaki H Tags: Bioorg Med Chem Lett Source Type: research

Discovery, semisynthesis and neurite outgrowth-promoting activity of novel merrillianone/cycloparviforalone based esters as neurotrophic agents.
Abstract Natural products (NPs) are very important sources for the development of new drugs. Merrillianone and cycloparvifloralone, isolated from the roots, stems, and fruits of Illicium henryi Diels, are two natural sesquiterpene compounds. In continuation of our effort to discovery more effective neurotrophic compounds from NPs, a series of novel merrillianone/cycloparviforalone based esters 2a-i, 3a-g and 3i-q were prepared and their structures were characterized by 1H NMR, 13C NMR and IR spectral analyses. Furthermore, the spatial structure of compound 2h was unambiguously confirmed by X-ray crystallography. T...
Source: Bioorganic and Medicinal Chemistry Letters - January 29, 2021 Category: Chemistry Authors: Wen T, Chu J, Cheng W, Fu Y, Hu F, Yang R, Guo Y, Zhang Y, Liu J Tags: Bioorg Med Chem Lett Source Type: research

Trivalent Sulfonium Compounds (TSCs): Tetrahydrothiophene-based amphiphiles exhibit similar antimicrobial activity to analogous ammonium-based amphiphiles.
Abstract Recent advances in the development of quaternary ammonium compounds (QACs) have focused on new structural motifs to increase bioactivity, but significantly less studied has been the change from ammonium- to sulfonium-based disinfectants. Herein, we report the synthesis of structurally analogous series of quaternary ammonium and trivalent sulfonium compounds (TSCs). The bioactivity profiles of these compounds generally mirror each other, and the antibacterial activity of sulfonium-based THT-18 was found to be comparable to the commercial disinfectant, BAC. The development of these compounds presents a new ...
Source: Bioorganic and Medicinal Chemistry Letters - January 28, 2021 Category: Chemistry Authors: Feliciano JA, Leitgeb AJ, Schrank CL, Allen RA, Minbiole KPC, Wuest WM, Carden RG Tags: Bioorg Med Chem Lett Source Type: research

Diosgenin-induced physicochemical effects on phospholipid bilayers in comparison with cholesterol.
In this study we investigated the effects of the common tetracyclic cores and the different side chains on the physicochemical properties of lipid bilayer membranes. Differential scanning calorimetry showed that DGN and Cho reduce the phase transition enthalpy to a similar extent. In 2H NMR, deuterated-DGN/Cho and POPC showed similar ordering in POPC bilayers, which revealed that DGN is oriented parallel to the membrane normal like Cho. It was suggested that the affinity of DGN-Cho in membrane is stronger than that of DGN-DGN or Cho-Cho interaction. 31P NMR of POPC in bilayers revealed that, unlike Cho, DGN altered the int...
Source: Bioorganic and Medicinal Chemistry Letters - January 28, 2021 Category: Chemistry Authors: Candice Ondevilla J, Hanashima S, Mukogawa A, Umegawa Y, Murata M Tags: Bioorg Med Chem Lett Source Type: research

Thiosemicarbazide binds with the dicopper center in the competitive inhibition of mushroom tyrosinase enzyme: Synthesis and molecular modeling of theophylline analogues.
PMID: 33513384 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - January 26, 2021 Category: Chemistry Authors: Bari A, Ghani U, Ali Syed S, Riazullah Tags: Bioorg Med Chem Lett Source Type: research

Structure based design, synthesis, and biological evaluation of imidazole derivatives targeting dihydropteroate synthase enzyme.
In this study, we have designed and synthesized 2-((5-acetyl-1-(phenyl)-4-methyl-1H-imidazol-2-yl)thio)-N-(4-((benzyl)oxy)phenyl) acetamide derivatives. Antimicrobial activities of all the imidazole derivatives have been examined against Gram-positive and Gram-negative bacteria and results showed that the conjugates have appreciable antibacterial activity. Besides, several analogous were evaluated for their in vitro antiresistant bacterial strains such as Extended-spectrum beta-lactamases (ESBL), Vancomycin-resistant Enterococcus (VRE), and Methicillin-resistant Staphylococcus aureus (MRSA). The SAR revealed that the 12l c...
Source: Bioorganic and Medicinal Chemistry Letters - January 26, 2021 Category: Chemistry Authors: Daraji DG, Rajani DP, Rajani SD, Pithawala EA, Jayanthi S, Patel HD Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and biological evaluation of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer.
In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC50 = 9.09 - 31.11 µM compared to the positive controls: bicalutamide (IC50 = 45.20- 51.61 µM) and enzalutamide (IC50 = 11.47- 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides usi...
Source: Bioorganic and Medicinal Chemistry Letters - January 26, 2021 Category: Chemistry Authors: Kandil SB, Kariuki BM, McGuigan C, Westwell AD Tags: Bioorg Med Chem Lett Source Type: research

Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration.
Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration. Bioorg Med Chem Lett. 2021 Jan 26;:127821 Authors: Fiolek T, Magyar CL, Wall TJ, Davies SB, Campbell MV, Savich CJ, Tepe JJ, Adam Mosey R Abstract Aggregates or oligomeric forms of many intrinsically disordered proteins (IDPs), including α-synuclein, are hallmarks of neurodegenerative diseases, like Parkinson's and Alzheimer's disease, and key contributors to their pathogenesis. Due to their disordered nature and therefore lack of...
Source: Bioorganic and Medicinal Chemistry Letters - January 26, 2021 Category: Chemistry Authors: Fiolek T, Magyar CL, Wall TJ, Davies SB, Campbell MV, Savich CJ, Tepe JJ, Adam Mosey R Tags: Bioorg Med Chem Lett Source Type: research

Fluorene/fluorenone carboxamide derivatives as selective light-up fluorophores for c-myc G-quadruplex.
lu Z Abstract The development of fluorescent dyes capable of selective recognition of G-quadruplexes is essential for studying its localization and biological functions. However, considering the G-quadruplex topologies may vary significantly, the synthesis of compounds showing both selectivity and strong fluorescence properties still remains a great challenge. Recently we have developed fluorene/fluorenone derivatives with structure-specific binding towards dsRNA, indicating its potential for structure-selective ligands. Herein, we report the synthesis of novel fluorene/fluorenone derivatives and their selectivit...
Source: Bioorganic and Medicinal Chemistry Letters - January 26, 2021 Category: Chemistry Authors: Duyar H, Portakal HS, Yalçın E, Kanat B, Doluca O, Seferoğlu Z Tags: Bioorg Med Chem Lett Source Type: research

Design, Synthesis, and Biological Evaluation of 1,3,6,7-Tetrahydroxyxanthone Derivatives as Phosphoglycerate Mutase 1 Inhibitors.
This study provides valuable information for further optimization of PGAM1 inhibitors with 1,3,6,7-tetrahydroxyxanthone backbone or de novo design of novel inhibitor. PMID: 33513389 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - January 26, 2021 Category: Chemistry Authors: Jiang K, Gao B, Yu J, Jiang L, Niu A, Jia Y, Meng T, Zhou L, Wang J Tags: Bioorg Med Chem Lett Source Type: research

Identification of Plasmodium falciparum Heat Shock 90 Inhibitors via Molecular Docking.
PMID: 33513390 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - January 26, 2021 Category: Chemistry Authors: Everson N, Bach J, Hammill JT, Falade MO, Rice AL, Kiplin Guy R, Eagon S Tags: Bioorg Med Chem Lett Source Type: research

The study on structure-activity relationship between chromone derivatives and inhibition of superoxide anion generating from human neutrophils.
Abstract Over activation of neutrophils has been linked to many inflammatory diseases; one of critical pathologic mechanisms is that generation and exocellular release of superoxide anion from neutrophils results in peripheral tissues damage. Besides, in this study, 2-(3,5-dimethoxyphenoxy)-5,7-dimethoxy-chromen-4-one (4), a 2-phexnoychromone from our compound bank, was demonstrated to have the moderate inhibitory effect on superoxide anion generating. Therefore, serial chromones substituted with phenols or 3-flourothiophenol were designed, synthesized, and examined for suppression of superoxide anion generation. ...
Source: Bioorganic and Medicinal Chemistry Letters - January 25, 2021 Category: Chemistry Authors: Chang YH, Shu-Yen F, Lai HY, Hwang TL, Hung HY Tags: Bioorg Med Chem Lett Source Type: research

The influence of calculated physicochemical properties of compounds on their ADMET profiles.
Abstract We analyzed the influence of calculated physicochemical properties of more than 20,000 compounds on their P-gp and BCRP mediated efflux, microsomal stability, hERG inhibition, and plasma protein binding. Our goal was to provide guidance for designing compounds with desired pharmacokinetic profiles. Our analysis showed that compounds with ClogP less than 3 and molecular weight less than 400 will have high microsomal stability and low plasma protein binding. Compounds with logD less than 2.2 and/or basic pKa larger than 5.3 are likely to be BCRP substrates and compounds with basic pKa less than 5.2 and/or a...
Source: Bioorganic and Medicinal Chemistry Letters - January 25, 2021 Category: Chemistry Authors: Ma S, McGann M, Enyedy IJ Tags: Bioorg Med Chem Lett Source Type: research

Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition.
Abstract GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pu...
Source: Bioorganic and Medicinal Chemistry Letters - January 25, 2021 Category: Chemistry Authors: Swidorski JJ, Jenkins S, Hanumegowda U, Parker DD, Beno BR, Protack T, Ng A, Gupta A, Shanmugam Y, Dicker IB, Krystal M, Meanwell NA, Regueiro-Ren A Tags: Bioorg Med Chem Lett Source Type: research

Ulmusakidian, a new coumarin glycoside and antifungal phenolic compounds from the root bark of Ulmus davidiana var. japonica.
Abstract Bioactivity-driven LC/MS-based phytochemical analysis of the root bark extract of Ulmus davidiana var. japonica led to the isolation of 10 compounds including a new coumarin glycoside derivative, ulmusakidian (1). The structure of the new compound was elucidated using extensive spectroscopic analyses via 1D and 2D NMR spectroscopic data interpretations, HR-ESIMS, and chemical transformation. The isolated compounds 1-10 were tested for their antifungal activity against human fungal pathogens Cryptococcus neoformans and Candida albicans. Compounds 9 and 10 showed antifungal activity against C. neoformans, w...
Source: Bioorganic and Medicinal Chemistry Letters - January 25, 2021 Category: Chemistry Authors: Alishir A, Sik Yu J, Park M, Kim JC, Pang C, Kyu Kim J, Su Jang T, Hee Jung W, Hyun Kim K Tags: Bioorg Med Chem Lett Source Type: research

Design, synthesis, characterization, and anticancer activity of a novel series of O-substituted chalcone derivatives.
Abstract A new series of O-substituted chalcone derivatives bearing an/a allyl-, prenyl- or propargyl-substituent at different positions of rings A and B and their derivatives as drug leads, was designed, synthesized, and characterized. The chalcone derivatives were synthesized via base catalyzed Claisen-Schmidt condensation in MeOH or EtOH solutions of appropriately substituted aromatic ketones with O-allyl, and O-propargylvanillin, respectively. The intermediates O-substituted phenylketone derivatives were firstly synthesized by nucleophilic substitution reaction. All the newly synthesized compounds were charact...
Source: Bioorganic and Medicinal Chemistry Letters - January 25, 2021 Category: Chemistry Authors: Ngameni B, Cedric K, Mbaveng AT, Erdoğan M, Simo I, Kuete V, Daştan A Tags: Bioorg Med Chem Lett Source Type: research