Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold.
Abstract We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative...
Source: Bioorganic and Medicinal Chemistry - September 16, 2019 Category: Chemistry Authors: Yamamoto K, Tamura T, Nakamura R, Hosoe S, Matsubara M, Nagata K, Kodaira H, Uemori T, Takahashi Y, Suzuki M, Saito JI, Ueno K, Shuto S Tags: Bioorg Med Chem Source Type: research

Developing new hybrid scaffold for urease inhibition based on carbazole-chalcone conjugates: Synthesis, assessment of therapeutic potential and computational docking analysis.
Abstract Although a diverse range of chemical entities offering striking therapeutic potential against urease enzyme has been reported, the key challenges (toxicity and safety) associated with these inhibitors create a large unmet medical need to unveil new, potent and safe inhibitors of urease enzyme. In this pursuit, the present study demonstrates the successful synthesis of carbazole-chalcone hybrids (4a-n) in good yields. The evaluation of the preliminary in vitro biological results showed that selected members of the investigated library of hybrid compounds possess excellent urease inhibitory efficacy. In par...
Source: Bioorganic and Medicinal Chemistry - September 16, 2019 Category: Chemistry Authors: Kazmi M, Khan I, Khan A, Halim SA, Saeed A, Mehsud S, Al-Harrasi A, Ibrar A Tags: Bioorg Med Chem Source Type: research

Design, synthesis and evaluation of structurally diverse chrysin-chromene-spirooxindole hybrids as anticancer agents.
Abstract A series of structurally diverse chrysin-chromene-spirooxindole hybrids were designed, synthesized via a Knoevenagel/Michael/cyclization of chrysin and isatylidene malononitrile derivatives through utilizing a hybrid pharmacophore approach. The newly synthesized compounds were evaluated for their in vitro anticancer activity, and most of the compounds showed stronger anti-proliferative activity than parent compound chrysin. In particular, compound 3e had the highest cytotoxicity towards A549 cells (IC50 = 3.15 ± 0.51 μM), and had better selectivity in A549 cells and normal MRC-5 cells....
Source: Bioorganic and Medicinal Chemistry - September 16, 2019 Category: Chemistry Authors: Zhang WH, Chen S, Liu XL, Feng TT, Yang WD, Zhou Y Tags: Bioorg Med Chem Source Type: research

Erratum to "Fluoroquinolones structural and medicinal developments (2013-2018): Where are we now?" [Bioorg. Med. Chem. 27 (2019) 3005-3060].
Erratum to "Fluoroquinolones structural and medicinal developments (2013-2018): Where are we now?" [Bioorg. Med. Chem. 27 (2019) 3005-3060]. Bioorg Med Chem. 2019 Sep 16;:115072 Authors: Suaifan GARY, Mohammed AAM PMID: 31537435 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - September 16, 2019 Category: Chemistry Authors: Suaifan GARY, Mohammed AAM Tags: Bioorg Med Chem Source Type: research

Synthesis and insecticidal activity studies of novel phenylpyrazole derivatives containing arylimine or carbimidate moiety.
Abstract Phenylpyrazole insecticides are successful for crop protection and public hygiene by blocking gamma-aminobutyric acid (GABA)-gated chloride channels and glutamate-gated chloride (GluCl) channels. A series of novel phenylpyrazoles containing arylimine or 1-methoxyaryl groups were designed and synthesized. The addition reaction of methanol to the imines 1-11 was investigated and the cayno addition products 13-15 were obtained. The compounds 1-15 were confirmed by 1H NMR and elemental analysis. The results of bioassay indicated that some compounds exhibited comparable bioactivity to fipronil against a broad ...
Source: Bioorganic and Medicinal Chemistry - September 9, 2019 Category: Chemistry Authors: Zhao Q, Sun R, Liu Y, Chen P, Li Y, Yang S, Wang Q Tags: Bioorg Med Chem Source Type: research

Tryptoline-based benzothiazoles re-sensitize MRSA to β-lactam antibiotics.
Tryptoline-based benzothiazoles re-sensitize MRSA to β-lactam antibiotics. Bioorg Med Chem. 2019 Sep 09;:115095 Authors: Wang X, Chen J, Wang W, Jaunarajs A, Wang X Abstract Resistance-modifying agents (RMAs) offer a promising solution to combat bacterial antibiotic resistance. Here we report the discovery and structure-activity relationships of a new class of RMAs with a novel tryptoline-based benzothiazole scaffold. Our most potent compound in this series (4ad) re-sensitizes multiple MRSA strains to cephalosporins at low concentrations (2 μg/mL) and has low mammalian cytotoxicity with a ha...
Source: Bioorganic and Medicinal Chemistry - September 9, 2019 Category: Chemistry Authors: Wang X, Chen J, Wang W, Jaunarajs A, Wang X Tags: Bioorg Med Chem Source Type: research

The discovery and optimization of a series of 2-aminobenzoxazole derivatives as ChemR23 inhibitors.
Abstract A structural class of 2-aminobenzoxazole derivatives possessing biphenyltetrazole was discovered to be potent human ChemR23 inhibitors. We initially tried to improve the potency of compound 1, which was found through in-house screening using the human plasmacytoid dendritic cell (pDC)-like cell line CAL-1. The introduction of a chiral methyl moiety at a benzylic position in a center of compound 1 showed a large impact on the inhibitory activity against calcium signaling of ChemR23 induced by the natural ligand chemerin. As a result of further investigations at the benzylic position, (R)-isomer 6b was foun...
Source: Bioorganic and Medicinal Chemistry - September 6, 2019 Category: Chemistry Authors: Imaizumi T, Kobayashi A, Otsubo S, Komai M, Magara M, Otsubo N Tags: Bioorg Med Chem Source Type: research

Synthesis and biological evaluation of calycanthaceous alkaloid analogs.
Abstract Starting from 9-methyl-1,2,3,4,9,9a-hexahydro-4aH-pyrido[2,3-b]indol-4a-ol, or indole-3-acetonitrile, 40 new calycanthaceous alkaloid analogs were synthesized in excellent yields. The prepared compounds were evaluated for biological activity against acetylcholinesterase and a broad range of plant pathogen fungi. The results of bioassays indicated that the majority of tested compounds displayed comparable or better in vitro bioactivity than the positive control. Notably, compounds b8 and b9 showed higher activity against Verticillium dahlia than chlorothalonil, with MIC values of 62.5 and 7.81 µg...
Source: Bioorganic and Medicinal Chemistry - September 5, 2019 Category: Chemistry Authors: Zheng S, Zhu R, Zhou X, Chen L, Bai H, Zhang J Tags: Bioorg Med Chem Source Type: research

Synthesis and exploration of 2-morpholino-4-phenylthiazol-5-yl acrylamide derivatives for their effects against carbonic anhydrase I, II, IX and XII isoforms as a non-sulfonamide class of inhibitors.
Abstract Novel series of 2-morpholino-4-phenylthiazol-5-yl acrylamide derivatives (8a-s) have been synthesized and explored as a non-sulfonamide class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The newly synthesized molecules were evaluated for their CA inhibitory potency against four isoforms: the cytosolic isozyme hCA I, II as well as trans-membrane tumor associated isoform hCA IX and hCA XII taking acetazolamide (AAZ) as standard drug. The results revealed that most of the compounds showed good activity against hCA II, IX, and XII whereas none of them were active against hCA I (Ki >100 μM). It...
Source: Bioorganic and Medicinal Chemistry - September 5, 2019 Category: Chemistry Authors: Swain B, Singh Digwal C, Angeli A, Alvala M, Singh P, Supuran CT, Arifuddin M Tags: Bioorg Med Chem Source Type: research

Highly hydrophilic 1,3-oxazol-5-yl benzenesulfonamide inhibitors of carbonic anhydrase II for reduction of glaucoma-related intraocular pressure.
Abstract Four inhibitors of human carbonic anhydrase II (hCA II) were designed based on the previously reported subnanomolar 1,3-oxazole-based sulfonamide inhibitors of the enzyme to incorporate primary and secondary amine functionality in the carboxamide side chain. The new hydrophilic compounds were found to inhibit the target isoform in sub-nanomolar to low nanomolar range with a good degree of selectivity to several other hCA isoforms. The hydrophilic character of these compounds is advantageous for intraocular residence time but not for corneal permeability which generally requires that a drug be sufficiently...
Source: Bioorganic and Medicinal Chemistry - September 4, 2019 Category: Chemistry Authors: Kalinin S, Valtari A, Ruponen M, Toropainen E, Kovalenko A, Nocentini A, Gureev M, Dar'in D, Urtti A, Supuran CT, Krasavin M Tags: Bioorg Med Chem Source Type: research

Synthesis, biological evaluation and molecular docking of 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs containing the piperazine moiety.
Abstract Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (3, 4, 5, 7, 8, 10, 11, 12, 16, 18, 21, 23, and 24) exhibited potent antagonistic potency against AR (inhibition>50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward ...
Source: Bioorganic and Medicinal Chemistry - August 28, 2019 Category: Chemistry Authors: Chen H, Zhang J, Hu P, Qian Y, Li J, Shen J Tags: Bioorg Med Chem Source Type: research

Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors.
uez S Abstract Soluble epoxide hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC50 ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsom...
Source: Bioorganic and Medicinal Chemistry - August 26, 2019 Category: Chemistry Authors: Codony S, Valverde E, Leiva R, Brea J, Isabel Loza M, Morisseau C, Hammock BD, Vázquez S Tags: Bioorg Med Chem Source Type: research

Synthesis, biological activities, and docking studies of d-pantolactone derivatives as novel FAS inhibitors.
Abstract A novel series of fatty acid synthase (FAS) inhibitors with D-(-)-pantolactone moiety and potential utility for the treatment of obesity were designed, synthesized and characterized, in which the structure of compound 3k was further confirmed by single X-ray diffraction. The mouse FAS inhibitory activity of synthesized compounds was evaluated. Major synthesized compounds (except 3g, 3i, 3k, 3l, and 3n) exhibited moderate FAS inhibitory properties with IC50 values in the range of 13.68 ± 1.52-33.19 ± 1.39 μM, reference inhibitor C75 has IC50 value of 13.86 ± 2.79 &mu...
Source: Bioorganic and Medicinal Chemistry - August 24, 2019 Category: Chemistry Authors: Fang H, He J, Ran T, Chen H, Jin W, Tang B, Hong Z, Fang M Tags: Bioorg Med Chem Source Type: research

A click chemistry approach for the synthesis of cyclic ureido tethered coumarinyl and 1-aza coumarinyl 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis H37Rv and their in silico studies.
Abstract Nucleoside bases like uracil, pharmacophoric triazoles and benzimidazolones have been used during the present study to design molecular matrices for antitubercular activity, employing Click Chemistry. Click triazoles 4/7/10 have been obtained by the reaction of 4-(Azidomethyl)-2H-chromen-2-ones/quinolin-2(1H)-ones 3 and propargyl ethers 2/6/9 derived from theophylline/6-methyl uracil/2-benzimidazolone respectively. In addition to spectral data structures have been confirmed by single crystal X-ray diffraction studies in case of uracil bis alkyne (6) and theophylline mono triazole (4c). Theophylline linked...
Source: Bioorganic and Medicinal Chemistry - August 24, 2019 Category: Chemistry Authors: Khanapurmath N, Kulkarni MV, Joshi SD, Anil Kumar GN Tags: Bioorg Med Chem Source Type: research

Novel lipid side chain modified exenatide analogs emerged prolonged glucoregulatory activity and potential body weight management properties.
Abstract Exenatide is known as the first marketed GLP-1 agonist for antidiabetic treatment, but it need twice injection a day because of its fast clearance. This work aims to prolong the half-life of exenatide by modified with novel lipid chain. Four optimized exenatide analogs named as Cys12-Exenatide (1-39)-NH2, Cys40-Exenatide (1-39)-NH2, Cys12-Tyr22-Gln24-Glu28-Arg35-Exenatide (1-39)-NH2 and Tyr22-Gln24-Glu28-Arg35-Cys40-Exenatide (1-39)-NH2 were selected and applied for conjugation. Then a series of evaluations including GLP-1R activation assay were conducted, conjugation C2 was selected for further investiga...
Source: Bioorganic and Medicinal Chemistry - August 23, 2019 Category: Chemistry Authors: Li C, Cai X, Dai Y, Liu C, Bi X, Zhou J, Li Q, Sun L, Huang W, Hou Z, Qian H Tags: Bioorg Med Chem Source Type: research

Synthesis and highly potent anti-inflammatory activity of licofelone- and ketorolac-based 1-arylpyrrolizin-3-ones.
o-Cevallos GA, Delgado F, Tamariz J Abstract Since NSAIDs are commonly used anti-inflammatory agents that produce adverse effects, there have been ongoing efforts to develop more effective and less toxic compounds. Based on the structure of the anti-inflammatory pyrrolizines licofelone and ketorolac, a series of 1-arylpyrrolizin-3-ones was synthesized. Also prepared was a series of substituted pyrroles, mimicking similar known anti-inflammatory agents. The anti-inflammatory activity of the test compounds was determined with a phorbol ester (TPA)-induced murine ear edema protocol. For the most active derivatives, 1...
Source: Bioorganic and Medicinal Chemistry - August 20, 2019 Category: Chemistry Authors: Madrigal DA, Escalante CH, Gutiérrez-Rebolledo GA, Cristobal-Luna JM, Gómez-García O, Hernández-Benitez RI, Esquivel-Campos AL, Pérez-Gutiérrez S, Chamorro-Cevallos GA, Delgado F, Tamariz J Tags: Bioorg Med Chem Source Type: research

Optimization and anti-inflammatory evaluation of methyl gallate derivatives as a myeloid differentiation protein 2 inhibitor.
In this study, we identified a novel compound 4k with the potent anti-inflammatory activity among 39 methyl gallate derivatives (MGDs). MGD 4k exhibited a high binding affinity to MD2, which in turn prevented the formation of the LPS/MD2/TLR4 complex. In addition, MGD 4k significantly reversed the upregulation of LPS-induced inflammatory mediators such as tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 in vitro and in vivo. Mechanistically, MGD 4k performed anti-inflammatory function by inactivating JNK, ERK and p38 s...
Source: Bioorganic and Medicinal Chemistry - August 19, 2019 Category: Chemistry Authors: Qiu Y, Xiao Z, Wang Y, Zhang D, Zhang W, Wang G, Chen W, Liang G, Li X, Zhang Y, Liu Z Tags: Bioorg Med Chem Source Type: research

A rational search for discovering potential neutraligands of human complement fragment 5a (hC5a).
Abstract The human complement fragment 5a (hC5a) is an extremely potent proinflammatory glycoprotein, which upon binding to C5aR triggers a plethora of immune and non-immunological responses in humans. Dysregulation of complement system is associated with the upregulation of hC5a, leading to the surge of proinflammatory cytokines, which further exacerbate the chronic inflammation induced pathological conditions. Thus, hC5a is considered as a major pharmacological target for developing complement therapeutics that can directly or indirectly modulate the function of hC5a. However, the idea of small molecules, direct...
Source: Bioorganic and Medicinal Chemistry - August 19, 2019 Category: Chemistry Authors: Mishra R, Rana S Tags: Bioorg Med Chem Source Type: research

Synthesis and fungicidal activity of novel pyrazole derivatives containing 5-Phenyl-2-Furan.
Abstract Pyrazole constitutes an important heterocyclic family covering a broad range of synthetic as well as natural products that exhibit numerous chemical, biological, agrochemical and pharmacological properties. In order to explore compounds with good fungicidal activity, a series of new pyrazole derivatives containing 5-phenyl-2-furan were designed and synthesized. In vitro and in vivo fungicidal activities were evaluated and the compound ethyl-1-(5-phenylfuran-2-carbonyl)-5-propyl-1H-pyrazole-3-carboxylate (I8) displayed significant fungicidal activity against various fungi, especially against P. infestans. ...
Source: Bioorganic and Medicinal Chemistry - August 16, 2019 Category: Chemistry Authors: Ahmed W, Yan X, Hu D, Adnan M, Tang RY, Cui ZN Tags: Bioorg Med Chem Source Type: research

Corrigendum to 'Betulinic acid induces apoptosis and inhibits metastasis of human colorectal cancer cells in vitro and in vivo' [Bioorg. Med. Chem. 27 (2019) 2546-2552].
PMID: 31416739 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - August 12, 2019 Category: Chemistry Authors: Zeng A, Hua H, Liu L, Zhao J Tags: Bioorg Med Chem Source Type: research

3-18F-fluoropropane-1-thiol and 18F-PEG4-1-thiol: Versatile prosthetic groups for radiolabeling maleimide functionalized peptides.
Abstract The efficient radiosynthesis of biomolecules utilizing minute quantities of maleimide substrate is important for availability of novel peptide molecular imaging agents. We evaluated both 3-18F-fluoropropane-1-thiol and 2-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)ethane-1-thiol (18F-fluoro-PEG4 thiol) as prosthetic groups for radiolabeling under physiological conditions. The precursor employed a benzoate for protection of the thiol and an arylsulfonate leaving group. The radiofluorination was fully automated on an Eckert & Ziegler synthesis system using standard Kryptofix222/K2CO3 conditions. In order to...
Source: Bioorganic and Medicinal Chemistry - August 5, 2019 Category: Chemistry Authors: Jacobson O, Wang Z, Yu G, Ma Y, Chen X, Kiesewetter DO Tags: Bioorg Med Chem Source Type: research

Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review.
Abstract Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both pate...
Source: Bioorganic and Medicinal Chemistry - August 1, 2019 Category: Chemistry Authors: Sangshetti J, Pathan SK, Patil R, Akber Ansari S, Chhajed S, Arote R, Shinde DB Tags: Bioorg Med Chem Source Type: research

Development of 99mTc radiolabeled A85380 derivatives targeting cerebral nicotinic acetylcholine receptor: Novel radiopharmaceutical ligand 99mTc-A-YN-IDA-C4.
Abstract Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (99mTc) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent α4β2-nAChR agonist, we prepared A85380 derivatives labeled w...
Source: Bioorganic and Medicinal Chemistry - July 31, 2019 Category: Chemistry Authors: Mori D, Kimura H, Kawashima H, Yagi Y, Arimitsu K, Ono M, Saji H Tags: Bioorg Med Chem Source Type: research

Effect of Panax ginseng combined with Angelica sinensis on the dissolution of ginsenosides and in chemotherapy mice hematopoietic function.
CONCLUSION: GA can ameliorate the hematopoietic function of mice after chemotherapy, and GA2:3, GA3:2 were the best, which may be due to the changes of the pharmacodynamic material basis of GA after compatibility. All these results implied that GA may be an ideal drug and food supplement for the treatment of toxic and side effects of chemotherapeutic drugs. PMID: 31395508 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - July 31, 2019 Category: Chemistry Authors: Zheng X, Fu Z, Wang C, Zhang S, Dai M, Cai E, Zhao Y Tags: Bioorg Med Chem Source Type: research

Novel epidithiodiketopiperazines as anti-viral zinc ejectors of the Feline Immunodeficiency Virus (FIV) nucleocapsid protein as a model for HIV infection.
Abstract Focused libraries of multi-substituted epidithiodiketopiperazines (ETP) were prepared and evaluated for efficacy of inhibiting the nucleocapsid protein function of the Feline Immunodeficiency Virus (FIV) as a model for HIV. This activity was compared and contrasted to observed toxicity utilising an in-vitro cell culture approach. This resulted in the identification of several promising lead compounds with nanomolar potency in cells with low toxicity and a favorable therapeutic index. PMID: 31395510 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - July 30, 2019 Category: Chemistry Authors: Asquith CRM, Sil BC, Laitinen T, Tizzard GJ, Coles SJ, Poso A, Hofmann-Lehmann R, Hilton ST Tags: Bioorg Med Chem Source Type: research

Structure-activity analysis of peptidic Chlamydia HtrA inhibitors.
This study details the strategies employed in optimizing the irreversible CtHtrA inhibitor JO146 [Boc-Val-Pro-ValP(OPh)2] for potency and selectivity. A series of adaptations both at the warhead and specificity residues P1 and P3 yielded 23 analogues, which were tested in human neutrophil elastase (HNE) and CtHtrA enzyme assays as well as Chlamydia cell culture assays. Trypsin and chymotrypsin inhibition assays were also conducted to measure off-target selectivity. Replacing the phosphonate moiety with α-ketobenzothiazole produced a reversible analogue with considerable CtHtrA inhibition and cell culture activity. Te...
Source: Bioorganic and Medicinal Chemistry - July 30, 2019 Category: Chemistry Authors: Agbowuro AA, Hwang J, Peel E, Mazraani R, Springwald A, Marsh JW, McCaughey L, Gamble AB, Huston WM, Tyndall JDA Tags: Bioorg Med Chem Source Type: research

Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability.
ska A Abstract On the basis of the structures of serotonin modulators or drugs (NAN-190, buspirone, aripiprazole) and phosphodiesterase 4 (PDE4) inhibitors (rolipram, RO-20-1724), a series of novel multitarget 5-arylidenehydantoin derivatives with arylpiperazine fragment was synthesized. Among these compounds, 5-(3,4-dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (13) and 5-(3-cyclopentyloxy-4-methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (18) were found to be the most promising showing very high affinity toward 5-HT1A an...
Source: Bioorganic and Medicinal Chemistry - July 30, 2019 Category: Chemistry Authors: Czopek A, Bucki A, Kołaczkowski M, Zagórska A, Drop M, Pawłowski M, Siwek A, Głuch-Lutwin M, Pękala E, Chrzanowska A, Struga M, Partyka A, Wesołowska A Tags: Bioorg Med Chem Source Type: research

Preparation and biological evaluation of soluble tetrapeptide epoxyketone proteasome inhibitors.
Abstract A series of novel tetrapeptidyl epoxyketone inhibitors of 20S proteasome was designed and synthesized. To fully understand the SAR, various groups at R1, R2, R3, R4 and R5 positions, including aromatic and aliphatic substituents were designed, synthesized and biologically assayed. Based on the enzymatic results, seven compounds were selected to evaluate their cellular activities and soluble compound 36 showed strong potency against human multiple myeloma (MM) cell lines. Microsomal stability results indicated that compound 36 was more stable in mice, rat and human microsomes than marketed carfilzomib. The...
Source: Bioorganic and Medicinal Chemistry - July 30, 2019 Category: Chemistry Authors: Lei M, Zhang H, Miao H, Du X, Zhou H, Wang J, Wang X, Feng H, Shi J, Liu Z, Shen J, Zhu Y Tags: Bioorg Med Chem Source Type: research

Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis.
ute;nior EN Abstract Isoniazid-naphthoquinone hybrids were synthesized and evaluated against a susceptible (H37Rv) strain and two isoniazid-resistant strains (INHR1 and INHR2) of Mycobacterium tuberculosis. The antimycobacterial activity of the derivatives was determined based on the resazurin microtiter assay and their cytotoxicity in adhered mouse monocyte macrophage J774.A1 cells (ATCC TIB-67). Of the twenty-two compounds evaluated against the three strains of M. tuberculosis, twenty-one presented some activity against the H37Rv and INHR1 (katG S315T) or INHR2 (inhA C(-5)T) strains. Compounds 1a, 2a, and 8a wer...
Source: Bioorganic and Medicinal Chemistry - July 27, 2019 Category: Chemistry Authors: Reis WJ, Bozzi ÍAO, Ribeiro MF, Halicki PCB, Ferreira LA, Almeida da Silva PE, Ramos DF, de Simone CA, da Silva Júnior EN Tags: Bioorg Med Chem Source Type: research

Design and synthesis of sulfonamidophenylethylamides as novel cardiac myosin activator.
Abstract The sulfonamidophenylethylamide analogues were explored for finding novel and potent cardiac myosin activators. Among them, N-(4-(N,N-dimethylsulfamoyl)phenethyl-N-methyl-5-phenylpentanamide (13, CMA at 10 µM = 48.5%; FS = 26.21%; EF = 15.28%) and its isomer, 4-(4-(N,N-dimethylsulfamoyl)phenyl-N-methyl-N-(3-phenylpropyl)butanamide (27, CMA at 10 µM = 55.0%; FS = 24.69%; EF = 14.08%) proved to be efficient cardiac myosin activators both in in vitro and in vivo studies. Compounds 13 (88.2 + 3.1% at 5 µM) and 27 (46.5 + 2.8% at 5 µM) showed posi...
Source: Bioorganic and Medicinal Chemistry - July 27, 2019 Category: Chemistry Authors: Manickam M, Pillaiyar T, Namasivayam V, Boggu PR, Sharma N, Jalani HB, Venkateswararao E, Lee YJ, Jeon ES, Son MJ, Woo SH, Jung SH Tags: Bioorg Med Chem Source Type: research

C-glyco"RGD" as αIIbβ3 and αvβ integrin ligands for imaging applications: Synthesis, in vitro evaluation and molecular modeling.
We report herein the development of linear and cyclic fluoro-C-glycoside"RGD" conjugates, taking advantage of the robustness and hydrophilicity of C-glycosides. As attested by in vitro evaluation, the design of these C-glyco"RGD" with a flexible three-carbon triazolyl linker allows distinct profiles towards αIIbβ3 and αvβ3 integrins. Molecular-dynamics simulations confirm the suitability of cyclic C-glyco-c(RGDfC) to target αvβ3 integrin. These C-glyco"RGD" could become promising biological tools in particular for Positron Emission Tomography imaging. PMID...
Source: Bioorganic and Medicinal Chemistry - July 25, 2019 Category: Chemistry Authors: Vucko T, Pétry N, Dehez F, Lambert A, Monari A, Lakomy C, Lacolley P, Regnault V, Collet C, Karcher G, Pellegrini-Moïse N, Lamandé-Langle S Tags: Bioorg Med Chem Source Type: research

Peptide derivatives as inhibitors of NS2B-NS3 protease from Dengue, West Nile, and Zika flaviviruses.
-Júnior JX Abstract Currently, more than 70 flaviviruses were identified and reported in the literature, whose Dengue (DENV), Zika (ZIKV), and West Nile (WNV) viruses have been responsible for millions of cases of infections worldwide, mainly in developing countries. These viruses are transmitted by the bite of mosquitoes from genus Aedes, or Culex and, in some cases, Stegomyia. Despite numerous efforts to identify a selective, safe, and effective antiviral agent, there is no currently approved drug for the treatment of flaviviral infections. Then, current pharmacological therapy has the objective to treat ...
Source: Bioorganic and Medicinal Chemistry - July 23, 2019 Category: Chemistry Authors: da Silva-Júnior EF, de Araújo-Júnior JX Tags: Bioorg Med Chem Source Type: research

Corrigendum to "Design and synthesis of 1,3-biarylsulfanyl derivatives as new anti-breast cancer agents" [Bioorg. Med. Chem. 19 (2011) 5409-5419].
Corrigendum to "Design and synthesis of 1,3-biarylsulfanyl derivatives as new anti-breast cancer agents" [Bioorg. Med. Chem. 19 (2011) 5409-5419]. Bioorg Med Chem. 2019 Jul 22;: Authors: Kumar A, Tripathi VD, Kumar P, Gupta LP, Akanksha, Trivedi R, Bid H, Nayak VL, Siddiqui JA, Chakravarti B, Saxena R, Dwivedi A, Siddiquee MI, Siddiqui U, Konwar R, Chattopadhyay N PMID: 31345744 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - July 22, 2019 Category: Chemistry Authors: Kumar A, Tripathi VD, Kumar P, Gupta LP, Akanksha, Trivedi R, Bid H, Nayak VL, Siddiqui JA, Chakravarti B, Saxena R, Dwivedi A, Siddiquee MI, Siddiqui U, Konwar R, Chattopadhyay N Tags: Bioorg Med Chem Source Type: research

Rational modification of Mannich base-type derivatives as novel antichagasic compounds: Synthesis, in vitro and in vivo evaluation.
Pérez-Silanes S Abstract The current chemotherapy against Chagas disease is inadequate and insufficient. A series of ten Mannich base-type derivatives have been synthesized to evaluate their in vitro antichagasic activity. After a preliminary screening, compounds 7 and 9 were subjected to in vivo assays in a murine model. Both compounds caused a substantial decrease in parasitemia in the chronic phase, which was an even better result than that of the reference drug benznidazole. In addition, compound 9 also showed better antichagasic activity during the acute phase. Moreover, metabolite excretion, effect o...
Source: Bioorganic and Medicinal Chemistry - July 19, 2019 Category: Chemistry Authors: Paucar R, Martín-Escolano R, Moreno-Viguri E, Azqueta A, Cirauqui N, Marín C, Sánchez-Moreno M, Pérez-Silanes S Tags: Bioorg Med Chem Source Type: research

Inhibitory effects of N-(acryloyl)benzamide derivatives on tyrosinase and melanogenesis.
Abstract Targeting of tyrosinase has proven to be the best means of identifying safe, efficacious, and potent tyrosinase inhibitors for whitening skin. We designed and synthesized ten NAB (N-(acryloyl)benzamide) derivatives (1a-1j) using the Horner-Wadsworth-Emmons olefination of diethyl (2-benzamido-2-oxoethyl)phosphonate and appropriate benzaldehydes. A mushroom tyrosinase inhibitory assay showed compounds 1a (36.71 ± 2.14% inhibition) and 1j (25.99 ± 2.77% inhibition) inhibited tyrosinase more than the other eight NAB derivatives and kojic acid (21.56 ± 2.93% inhibition), and do...
Source: Bioorganic and Medicinal Chemistry - July 19, 2019 Category: Chemistry Authors: Lee S, Ullah S, Park C, Won Lee H, Kang D, Yang J, Akter J, Park Y, Chun P, Moon HR Tags: Bioorg Med Chem Source Type: research

COX-1/COX-2 inhibition activities and molecular docking study of newly designed and synthesized pyrrolo[3,4-c]pyrrole Mannich bases.
Abstract In the present paper we describe the biological activity of newly designed and synthesized series of pyrrolo[3,4-c]pyrrole Mannich bases (7a-n). The Mannich bases were obtained in good yields by one-pot, three-component condensation of pyrrolo[3,4-c]pyrrole scaffold (6a-c) with secondary amines and an excess of formaldehyde solution in C2H5OH. The chemical structures of the compounds were characterized by 1H NMR, 13C NMR, FT-IR, and elemental analysis. Moreover, single crystal X-ray diffraction has been recorded for compound 7l. All synthesized derivatives were investigated for their potencies to inhibit ...
Source: Bioorganic and Medicinal Chemistry - July 19, 2019 Category: Chemistry Authors: Redzicka A, Szczukowski Ł, Kochel A, Wiatrak B, Gębczak K, Czyżnikowska Ż Tags: Bioorg Med Chem Source Type: research

Structure-aided optimization of 3-O- β-chacotriosyl ursolic acid as novel H5N1 entry inhibitors with high selective index.
This study indicated that the attachment of the methoxy group or Cl atom to the phenyl ring at the ortho- or para-position was crucial to improve inhibitory activity. Mechanism studies demonstrated that these title triterpenoids could bind tightly to the viral envelope HA to block the attachment of viruses to host cells, which was consistent with docking studies. PMID: 31350154 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - July 19, 2019 Category: Chemistry Authors: Liao Y, Chen L, Li S, Cui ZN, Lei Z, Li H, Liu S, Song G Tags: Bioorg Med Chem Source Type: research

Natural product-inspired profluorophores for imaging NQO1 activity in tumour tissues.
ute;nior EN Abstract Herein we designed a collection of trimethyl-lock quinone profluorophores as activity-based probes for imaging NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells and tumour tissues. Profluorophores were prepared via synthetic routes from naturally-occurring quinones and characterised in vitro using recombinant enzymes, to be further validated in cells and fresh frozen canine tumour tissues as potential new tools for cancer detection and imaging. PMID: 31327676 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - July 15, 2019 Category: Chemistry Authors: Cheng Z, Valença WO, Dias GG, Scott J, Barth ND, de Moliner F, Souza GBP, Mellanby RJ, Vendrell M, da Silva Júnior EN Tags: Bioorg Med Chem Source Type: research

Identification and characterization of the first fragment hits for SETDB1 Tudor domain.
mith CH Abstract SET domain bifurcated protein 1 (SETDB1) is a human histone-lysine methyltransferase which is amplified in human cancers and was shown to be crucial in the growth of non-small and small cell lung carcinoma. In addition to its catalytic domain, SETDB1 harbors a unique tandem tudor domain which recognizes histone sequences containing both methylated and acetylated lysines, and likely contributes to its localization on chromatin. Using X-ray crystallography and NMR spectroscopy fragment screening approaches, we have identified the first small molecule fragment hits that bind to histone peptide bindin...
Source: Bioorganic and Medicinal Chemistry - July 12, 2019 Category: Chemistry Authors: Mader P, Mendoza-Sanchez R, Iqbal A, Dong A, Dobrovetsky E, Corless VB, Liew SK, Houliston SR, De Freitas RF, Smil D, Sena CCD, Kennedy S, Diaz DB, Wu H, Dombrovski L, Allali-Hassani A, Min J, Schapira M, Vedadi M, Brown PJ, Santhakumar V, Yudin AK, Arrow Tags: Bioorg Med Chem Source Type: research

Natural product derived promising anti-MRSA drug leads: A review.
Abstract Multi-drug resistant Staphylococcus aureus infections have created a critical need for the development of new classes of antibacterials. Discovery of new naturally derived antibacterial agents with new mechanism of action remains a high priority globally. Several of the available antibacterial agents like β-lactams, polyketides, phenylpropanoids, aminoglycosides, macrolides, glycopeptides, streptogramins and lipopeptides are natural products or their semisynthetic variations. In the current scenario of alarming rise in antibacterial resistance, revisiting natural products with modern chemistry and bi...
Source: Bioorganic and Medicinal Chemistry - July 12, 2019 Category: Chemistry Authors: Gatadi S, Gour J, Nanduri S Tags: Bioorg Med Chem Source Type: research

Discovery of fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one as VDR signaling regulators.
In this study we discovered by luciferase reporter assay that several fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one with the assistance of calcitriol result in up to three-fold increases of VDR promoter activity. Preliminary SAR results from 20 compounds disclose that ideal VDR signaling regulators of these compounds are built up by the optimal combination of multiple factors. Western blot analysis indicates that compounds of ZD-3, ZD-4 and ZD-5 not only significantly upregulate p62 and LC3-II but also elevate the ratio of LC3-II/LC3-I, which possibly leads to activated autophagy. All of five compounds also...
Source: Bioorganic and Medicinal Chemistry - July 12, 2019 Category: Chemistry Authors: Xu B, Ding MY, Weng Z, Li ZQ, Li F, Sun X, Chen QL, Wang YT, Wang Y, Zhou GC Tags: Bioorg Med Chem Source Type: research

Cyclic heptapeptides from the soil-derived fungus Clonostachys rosea.
h P Abstract Three new cyclic heptapeptides (1-3) together with three known compounds (4-6) were isolated from a solid rice culture of the soil-derived fungus Clonostachys rosea. Fermentation of the fungus on white beans instead of rice afforded a new γ-lactam (7) and a known γ-lactone (8) that were not detected in the former extracts. The structures of the new compounds were elucidated on the basis of 1D and 2D NMR spectra as well as by HRESIMS data. Compounds 1 and 4 exhibited significant cytotoxicity against the L5178Y mouse lymphoma cell line with IC50 values of 4.1 and 0.1 µM, respectively...
Source: Bioorganic and Medicinal Chemistry - July 12, 2019 Category: Chemistry Authors: Abdel-Wahab NM, Harwoko H, Müller WEG, Hamacher A, Kassack MU, Fouad MA, Kamel MS, Lin W, Ebrahim W, Liu Z, Proksch P Tags: Bioorg Med Chem Source Type: research

Upregulation of p53 through induction of MDM2 degradation: Anthraquinone analogs.
In this study, we systematically investigated the effect of substitution patterns of the core anthraquinone scaffold. Through cytotoxicity evaluation in two leukemia cell lines, the structure-activity relationship of thirty-two analogs has been examined. Several analogs with comparable or improved potency over BW-AQ-101 have been identified. Western-blot assays verified the effect of the potent compounds on the MDM2-p53 axis. The study also suggests new chemical space for further optimization work. PMID: 31324563 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - July 11, 2019 Category: Chemistry Authors: Draganov AB, Yang X, Anifowose A, De La Cruz LKC, Dai C, Ni N, Chen W, De Los Santos Z, Gu L, Zhou M, Wang B Tags: Bioorg Med Chem Source Type: research

Phenylhydrazides as inhibitors of Leishmania amazonensis arginase and antileishmanial activity.
va ER Abstract Searching for new substances with antileishmanial activity, we synthesized and evaluated a series of α,α-difluorohydrazide and α,α-difluoramides against Leishmania amazonensis arginase (LaArg). Four α,α-difluorohydrazide derivatives showed activity against LaArg with Ki in the range of 1.3-26 μM. The study of the kinetics of LaArg inhibition showed that these substances might act via different inhibitory mechanisms or even by a combination of these. The compounds were tested against L. amazonensis promastigotes and the best result was obtained to the compound...
Source: Bioorganic and Medicinal Chemistry - July 11, 2019 Category: Chemistry Authors: Crizanto de Lima E, Castelo-Branco FS, Maquiaveli CC, Farias AB, Rennó MN, Boechat N, Silva ER Tags: Bioorg Med Chem Source Type: research

Optimization and biological evaluation of nicotinamide derivatives as Aurora kinase inhibitors.
Abstract Aurora kinases are known to be overexpressed in various solid tumors and implicated in oncogenesis and tumor progression. A series of nicotinamide derivatives were synthesized and their biological activities were evaluated, including kinase inhibitory activity against Aur A and Aur B and in vitro antitumor activity against SW620, HT-29, NCI-H1975 and Hela cancer cell lines. In addition, the study of antiproliferation, cytotoxicity and apoptosis was performed meanwhile. As the most potent inhibitor of Aur A, 4-((3-bromo-4-fluorophenyl)amino)-6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)ni...
Source: Bioorganic and Medicinal Chemistry - July 11, 2019 Category: Chemistry Authors: Qi B, Xu X, Yang Y, He H, Yue X Tags: Bioorg Med Chem Source Type: research

Synthesis, pharmacological evaluation, and mechanistic study of adefovir mixed phosphonate derivatives bearing cholic acid and l-amino acid moieties for the treatment of HBV.
Abstract The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono l-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na+-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 6c as the optimal ...
Source: Bioorganic and Medicinal Chemistry - July 8, 2019 Category: Chemistry Authors: Li T, Li J, Yang Y, Han Y, Wu D, Xiao T, Wang Y, Liu T, Zhao Y, Li Y, Dai Z, Fu X Tags: Bioorg Med Chem Source Type: research

Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors.
Abstract Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced workin...
Source: Bioorganic and Medicinal Chemistry - July 6, 2019 Category: Chemistry Authors: Chino A, Honda S, Morita M, Yonezawa K, Hamaguchi W, Amano Y, Moriguchi H, Yamazaki M, Aota M, Tomishima M, Masuda N Tags: Bioorg Med Chem Source Type: research

2-(Bipiperidin-1-yl)-5-(nitroaryl)-1,3,4-thiadiazoles: Synthesis, evaluation of in vitro leishmanicidal activity, and mechanism of action.
Abstract The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of Leishmania major (L. major). Amongst the synthesized compounds, 2-([1,4'-bipiperidin]-1'-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (IIa) and 1-(5-(1-methyl-5-nitro-1H-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(...
Source: Bioorganic and Medicinal Chemistry - July 5, 2019 Category: Chemistry Authors: Mojallal-Tabatabaei Z, Foroumadi P, Toolabi M, Goli F, Moghimi S, Kaboudanian-Ardestani S, Foroumadi A Tags: Bioorg Med Chem Source Type: research

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview.
Abstract The 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These five-membered heterocyclic motifs with three nitrogen heteroatoms can be prepared easily using 'click' chemistry with copper- or ruthenium-catalysed azide-alkyne cycloaddition reactions. Recently, the 'linker' property of 1,2,3-triazoles was demonstrated, and a novel class of 1,2,3-triazole-containing hybrids and conjugates was synthesised and evaluated as lead compounds for diverse biological targets. These lead compounds have been demonstrated as anticancer, antimicrobial, anti-tubercular, antiviral, an...
Source: Bioorganic and Medicinal Chemistry - July 4, 2019 Category: Chemistry Authors: Bozorov K, Zhao J, Aisa HA Tags: Bioorg Med Chem Source Type: research

Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii.
Abstract As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 21-33), that is, the position of the amino group was one carbon closer to the gem-...
Source: Bioorganic and Medicinal Chemistry - July 4, 2019 Category: Chemistry Authors: Galaka T, Falcone BN, Li C, Szajnman SH, Moreno SNJ, Docampo R, Rodriguez JB Tags: Bioorg Med Chem Source Type: research