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The synthetic strategy for the benzothiazole-benzonitrile chromophore 6 involved three sequences of reactions. It was initiated by condensation of 2-amino-4-nitrothiophenol (2) with 4-(piperidin-1-yl)benzaldehyde (1) to produce the corresponding 5-nitrobenzothiazole compound 3 followed by reduction of compound 3 into the 5-aminobenzothiazole compound 4 and then ended by condensation of 5-aminobenzothiazole compound 4 with 4-formylbenzonitrile (5). The chromophore's absorption and emission spectra have been measured in EtOH and presented good Stokes' shift ( ∆ ν ¯ $$ \Delta \overline{\nu} $$  = 8363 cm -1 ). The DFT configuration of the frontier molecular orbits in gas and solvated ground state (S o ) were compared with the solvated excited state (S 1 ). The synthesized chromophore 6 was assessed for its antimicrobic properties against a group of bacterial and fungal strains. The minimum inhibitory concentration (MIC) values were determined using standard broth microdilution assay. Notably, chromophore 6 exhibited remarkable MIC values against Staphylococcus aureus and Escherichia coli (< 48 and < 118 μg/mL). Regarding the antibacterial effectiveness against both S. aureus and E. coli, molecular docking was performed to simulate their binding interactions with two protein structures, PDB:2eg7 and PDB:3u2k. The SwissADME study has been applied to explore the pharmacokinetic and pharmacodynamic characteristics of chromophore 6., (© 2024 John Wiley & Sons Ltd.)

Committed to our growing effort addressed toward the development of potent anti-breast cancer candidates, new 4-hydrazinylpyrimidine-5-carbonitriles featuring a morpholinyl or piperidinyl moiety at the position-2 and derivatized with various functionalities at the hydrazinyl group were designed through structure optimization, and their antiproliferative potency against two human breast cancer (BC) cell lines, relative to the reference drug 5-FU, was evaluated. Compounds showing remarkable cytotoxic activity versus the hormone dependent MCF-7 cell line (IC 50  = 1.62 ± 0.06 µM- 9.88 ± 0.38 µM) and the non-hormone dependent MDA-MB-231 cell line (IC 50  = 3.26 ± 0.14 µM-12.93 ± 0.55 µM) were further tested by multiple assays for clarification of their potential activity. Promising derivatives revealing low damage to healthy cells were subject to enzymatic inhibitory assessment against ARO and EGFR and their activities compared to letrozole and erlotinib respectively. Compounds 3c, 6a as well as compounds 4c, 4d proved to be good inhibitors of the ARO and EGFR enzymes respectively. Active compounds were also evaluated for their underlying mode of action by further investigation for CDK, Hsp90, PI3K inhibition and compared to normal MCF-10A cells and assessed for their enhancement of the caspase 9 levels. Additionally, cell cycle analysis and apoptotic induction were performed. They demonstrated remarkable activities in the previous assays and emanated as leads as anti-breast cancer candidates. Eventually, molecular docking analysis revealed that hit compounds 3c, 4c, 4d, and 6a could bind favorably to the proposed in silico models of various protein-ligand interactions. Therefore, our promising top candidates, by demonstrating appreciable anti-breast cancer activities, present valuable prospects for optimization, potency enhancement and future application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

β-Galactosidase (β-Gal) as an important glycoside hydrolase plays an important role in the early diagnosis of ovarian cancer. It is important to accurately and conveniently detect β-Gal in organisms. In this study, we developed a fluorescent probe TCF-GAL based on the tricyanofuran structure, which is linked to β-galactose through ether bonds for β-Gal detection. Probe TCF-GAL exhibited satisfactory selectivity and sensitivity toward β-Gal with the calculated LOD of 1.45 × 10 -4 U/mL. Moreover, it can be applied to image endogenous β-Gal in living SKOV3 cells with low cytotoxicity. Importantly, probe TCF-GAL was successfully employed in monitoring β-Gal in the mouse subcutaneous model of ovarian cancer. These results indicated that this probe had great potential for diagnosing β-Gal related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The optimization of hit compounds into drug candidates is a pivotal phase in drug discovery but often hampered by cumbersome manual synthesis of derivatives. While automated organic molecule synthesis has enhanced efficiency, safety, and cost-effectiveness, achieving fully automated multistep synthesis remains a formidable challenge due to issues such as solvent and reagent incompatibilities and the accumulation of side-products. We herein demonstrate an automated solid-phase flow platform for synthesizing α-keto-amides and nitrile peptidomimetics, guided by docking simulations, to identify potent broad-spectrum antiviral leads. A compact parallel synthesizer was built in-house, capable of producing 5 distinct molecules per cycle; 525 reactions could be finished within three months to generate 42 derivatives for a structure-activity relationship (SAR) investigation. Among these, ten derivatives exhibited promising target inhibitory activity (IC 50 < 100 nM) including two with antiviral activity (EC 50 < 250 nM). The platform, coupled with digital chemical recipe files, offers rapid access to a wide range of peptidomimetics, serving as a valuable reservoir for broad-spectrum antiviral candidates. This automated solid-phase flow synthesis approach expedites the generation of previously difficult complex molecular scaffolds. By integration of SPS-flow synthesis with medicinal chemistry campaign, >10-fold target inhibitory activity was achieved from a small set of derivatives, which indicates the potential to shift the paradigm of drug discovery.

Candida albicans (C. albicans) biofilm infections are quite difficult to manage due to their resistance against conventional antifungal drugs. To address this issue, there is a desperate need for new therapeutic drugs. In the present study, a green and efficient protocol has been developed for the synthesis of 2-amino-4H-pyran-3-carbonitrile scaffolds 4a-i, 6a-j, and 8a-g by Knoevenagel-Michael-cyclocondensation reaction between aldehydes, malononitrile, and diverse enolizable C-H activated acidic compounds using guanidinium carbonate as a catalyst either under grinding conditions or by stirring at room temperature. This protocol is operationally simple, rapid, inexpensive, has easy workup and column-free purification. A further investigation of the synthesized compounds was conducted to examine their antifungal potential and their ability to inhibit the growth and development of biofilm-forming yeasts like fungus C. albicans. According to our findings, 4b, 4d, 4e, 6e, 6f, 6g, 6i, 8c, 8d, and 8g were found to be active and potential inhibitors for biofilm infection causing C. albicans. The inhibition of biofilm by active compounds were observed using field emission scanning electron microscopy (FESEM). Biofilm inhibiting compounds were also tested for in vitro toxicity by using 3T3-L1 cell line, and 4b, 6e, 6f, 6g, 6i, 8c, and 8d were found to be biocompatible. Furthermore, the in silico ADME descriptors revealed drug-like properties with no violation of Lipinski's rule of five. Hence, the result suggested that synthesized derivatives could serve as a useful aid in the development of novel antifungal compounds for the treatment of fungal infections and virulence in C. albicans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Three new series of 3-(substituted)methylthio-4-cyano-5,6,7,8-tetrahydroisoquinolines were designed and synthesized starting from readily available materials, 7-acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-pyridyl, 3-pyridyl, phenyl, 4-methoxyphenyl, or 4-chlorophenyl)-5,6,7,8-tetrahydrosoquinoline-3(2 H )-thiones 2a - e in high yields and very pure states. Thus, compounds 2a - e were reacted with some chloro reagents, namely, N -aryl-2-chloroacetamides 3a - f and N -(naphthalen-2-yl)-2-chloroacetamide ( 3g ) under mild basic conditions to give the first two series of the target compounds, 3-( N -aryl)carbamoylmethylthio-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles 4a - l and 5a - e , respectively. Reaction of compounds 2d , e with ethyl chloroacetate under the same conditions gave the other series, 3-ethoxycarbonyl-methylthio-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles 6d , e . Structural formulas of all of the new compounds were elucidated and confirmed by elemental and spectral analyses. The insecticidal activity of all synthesized 5,6,7,8-tetrahydrosoquinolines toward the nymphs and adults of Aphis gossypii were screened. The results revealed the promising insecticidal activity of some tested compounds. Moreover, the structure-activity relationships as well as molecular docking of some representative compounds were evaluated.

A series of seleno-containing polyfunctionalized compounds was synthesized exploring cyanohydrin chemistry, including α-hydroxy esters, α-hydroxy acids, 1,2-diols, and 1,2-diacetates, with yields ranging from 26 up to 99 %. The cytotoxicity of all synthesized compounds was then evaluated using a non-tumor cell line (BALB/3T3 murine fibroblasts), and those deemed non-cytotoxic had their anti-melanoma activity evaluated using B16-F10 murine melanoma cells. These assays identified two compounds with selective cytotoxic activity against the tested melanoma cell line, showing a potential anti-melanoma application., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leandro Piovan reports financial support was provided by Federal University of Parana. Leandro Piovan reports a relationship with Federal University of Parana that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Organic fluorescent materials with red/near-infrared (NIR) emission are highly promising for use in biotechnology due to their exceptional advantages. However, traditional red/NIR fluorophores often exhibit weak emission at high concentrations or in an aggregated state due to the aggregate-caused quenching effect, which severely limits their applicability in biological imaging. To address this challenge, we developed a series of cyanostyrene derivatives with aggregation-induced emission characteristics, including 2,3-Bis-(4-styryl-phenyl)-but-2-enedinitrile (DPB), 2,3-Bis-{4-[2-(4-methoxy- phenyl)-vinyl]-phenyl}-but-2-enedinitrile (DOB), 2,3-Bis-{4-[2-(4-diphenylamino- phenyl)-vinyl]-phenyl}-but-2-enedinitrile (DTB), and 2,3-Bis-[4-(2-{4-[phenyl- (4-triphenylvinyl-phenyl)-amino]-phenyl}-vinyl)- phenyl]-but-2-enedinitrile (DTTB). Notably, these compounds exhibited intense solid state fluorescence owing to AIE effect, especially DTTB shows NIR emission with high solid state quantum efficiency (712 nm, Φ F =14.2 %). Then we prepared DTTB@PS-PEG NPs nanoparticles by encapsulating DTTB with the amphiphilic polymer polystyrene-polyethylene glycol (PS-PEG). Importantly, DTTB@PS-PEG NPs exhibited highly efficient NIR luminescence (Φ F =28.7 %) and a large two-photon absorption cross-section (1900 GM) under 800 nm laser excitation. The bright two-photon fluorescence of DTTB@PS-PEG indicated that it can be a highly promising candidate for two-photon fluorescence probe. Therefore, this work provides valuable insights for the design of highly efficient and NIR-emitting two-photon fluorescent probes., (© 2024 Wiley-VCH GmbH.)

In the search for new small molecules for the therapy of neuropathic pain, we found that 2-{3-[N-(1-benzylpiperidin-4-yl)propyl]amino}-6-[N-methyl-N-(prop-2-yn-1-yl)amino]-4-phenylpyridine-3,5-dicarbonitrile (12) induced a robust antiallodynic effect in capsaicin-induced mechanical allodynia, a behavioural model of central sensitization, through σ 1 R antagonism. Furthermore, administration of compound 12 to neuropathic animals, fully reversed mechanical allodynia, increasing its mechanical threshold to levels that were not significantly different from those found in paclitaxel-vehicle treated mice or from basal levels before neuropathy was induced. Ligand 12 is thus a promising hit-compound for the therapy of neuropathic pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4'-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N 3 -OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91-98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

9-cyanopyronin is a promising scaffold that exploits resonance Raman enhancement to enable sensitive, highly multiplexed biological imaging. Here, we developed cyano-Hydrol Green (CN-HG) derivatives as resonance Raman scaffolds to expand the color palette of 9-cyanopyronins. CN-HG derivatives exhibit sufficiently long wavelength absorption to produce strong resonance Raman enhancement for near-infrared (NIR) excitation, and their nitrile peaks are shifted to a lower frequency than those of 9-cyanopyronins. The fluorescence of CN-HG derivatives is strongly quenched due to the lack of the 10th atom, unlike pyronin derivatives, and this enabled us to detect spontaneous Raman spectra with high signal-to-noise ratios. CN-HG derivatives are powerful candidates for high performance vibrational imaging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Given the crucial role of the main protease (M pro ) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of M pro . Our systematic approach combined an M pro active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent M pro inhibitor 84 with an IC 50 value of 3.23 nM and a second-order rate constant of inactivation, k inac / K i , of 448,000 M -1 s -1 . The open-chain M pro inhibitor 58 , along with the macrocyclic compounds 83 and 84 , a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC 50 values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic M pro inhibitors as anti-SARS-CoV-2 agents.

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.

In this study, we present a comprehensive investigation of 2-amino-4,6-diphenylnicotinonitriles (APNs, 1 - 6 ), including their synthesis, cytotoxicity against breast cancer cell lines, and photophysical properties. Compound 3 demonstrates exceptional cytotoxicity, surpassing the potency of Doxorubicin. The fluorescence spectra of the synthesized 1 - 6 in different solvents reveal solvent-dependent shifts in the emission maximum values, highlighting the influence of the solvent environment on their fluorescence properties. A quantum chemical TD-DFT analysis provides insights into the electronic structure and fluorescence behavior of 1 - 6 , elucidating HOMO-LUMO energy gaps, electronegativity values, and dipole moments, contributing to a deeper understanding of their electronic properties and potential reactivity. These findings provide valuable knowledge for the development of APNs ( 1 - 6 ) as fluorescent sensors and potential anticancer agents.

Background: Diabetes is characterized by a lack of insulin and insensitivity to insulin. In 2013, the global diabetes population was 382 million, with 90% of them having type 2 diabetes (non-insulin-dependent). It is predicted that this number will increase to 592 million by 2035. Aim: Here, we aimed to synthesize a series of benzimidazole-based derivatives B1 - B32 with α-glucosidase inhibition potential as antidiabetic agents. Methods: Compounds B1 - B32 were prepared in three three-step reactions, and the structures were elucidated using spectroscopic methods, namely 1H NMR, 13C NMR, MS and IR. Enzyme inhibition and kinetic study were done using commercial assay kits, and molecular docking study using autodock4. Results: Bioassay data showed that twenty-four out of the thirty-two tested compounds exhibited IC50 values ranging from 44 to 745 μM, surpassing the standard molecule, acarbose (IC50: 750 μM). it was determined that the best compound, B10 , functions as a competitive inhibitor. Additionally, a molecular docking study provided insights into the interactions between the four most promising compounds ( B5 , B6 , B10 and B28 ) and the active site residues within the enzyme. Conclusion: The tested compounds are interesting α-glucosidase inhibitors, which indicates the benefit of more bioassay studies, especially in vivo studies.

Metallo-β-lactamases (MBLs) are a group of Zn(II)-dependent enzymes that pose a major threat to global health. They are linked to an increasing number of multi-drug resistant bacterial pathogens, but no clinically useful inhibitor is yet available. Since β-lactam antibiotics, which are inactivated by MBLs, constitute ∼65% of all antibiotics used to treat infections, the search for clinically relevant MBL inhibitors is urgent. Here, derivatives of a 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (1a) were synthesised and their inhibitory effects assessed against prominent representatives of the MBL family. Several compounds are potent inhibitors of each MBL tested, making them promising candidates for the development of broad-spectrum drug leads. In particular, compound 5f is highly potent across the MBL family, with K i values in the low µM range. Furthermore, this compound also appears to display synergy in combination with antibiotics such as penicillin G, cefuroxime or meropenem. This molecule thus represents a promising starting point to develop new drugs to inhibit a major mechanism of antibiotic resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Deuterium ( 2 H, D) is a stable isotope of hydrogen ( 1 H). Deuterium-incorporated (labelled) compounds are widely utilized in various scientific fields such as mechanistic studies of organic reactions, elucidation of drug metabolism, application as tracers for microanalysis. Recently, development of heavy drugs and molecular imaging using techniques such as neutron scattering and Raman spectroscopy are spotlighted. We have developed various deuterium-incorporated compounds using D 2 O as an inexpensive deuterium source to construct novel functional materials. The use of platinum group metals on carbon as catalysts could result in the multi-deuteration of compounds in the mixed solvents of 2-propanol and D 2 O, and site-selectively deuterated compounds can be synthesized by organocatalytic methods. In this review, the latter deuteration methods using organocatalysts and their applications are summarized. Terminal alkynes smoothly underwent deuterium incorporation by using triethylamine as an organic base or a solid resin possessing the tertiary amine moiety in the same molecule to give mono-deuterated alkynes. These compounds were partially reduced over our prepared specific palladium catalyst under atmospheric D 2 gas to produce tri-deuterated alkenes. Achiral or chiral di-deuterated β-nitro alcohols were also prepared by the organic-base-catalyzed deuteration of nitromethane, followed by nitroaldol reactions in a one pot manner. The mono-deuteration of aromatic aldehyde could be effectively catalyzed by N-heterocyclic carbene. Furthermore, the α-deuteration of aliphatic aldehydes using a basic resin catalyst and the subsequent Knoevenagel condensation with malononitrile could provide γ-deuterium-incorporated α,β-unsaturated nitrile derivatives. The deuterated compounds thus obtained can be important synthetic precursors to construct the deuterium-incorporated target functional materials.

Human dihydroorotate dehydrogenase ( h DHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as h DHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC 50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC 50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited h DHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t . Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of h DHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.

New cyanobenzofurans derivatives 2-12 were synthesised, and their antiproliferative activity was examined compared to doxorubicin and Afatinib (IC 50 = 4.17-8.87 and 5.5-11.2 µM, respectively). Compounds 2 and 8 exhibited broad-spectrum activity against HePG2 (IC 50 = 16.08-23.67 µM), HCT-116 (IC 50 = 8.81-13.85 µM), and MCF-7 (IC 50 = 8.36-17.28 µM) cell lines. Compounds 2 , 3 , 8 , 10 , and 11 were tested as EGFR-TK inhibitors to demonstrate their possible anti-tumour mechanism compared to gefitinib (IC 50 = 0.90 µM). Compounds 2 , 3 , 10 , and 11 displayed significant EGFR TK inhibitory activity with IC 50 of 0.81-1.12 µM. Compounds 3 and 11 induced apoptosis at the Pre-G phase and cell cycle arrest at the G2/M phase. They also increased the level of caspase-3 by 5.7- and 7.3-fold, respectively. The molecular docking analysis of compounds 2 , 3 , 10 , and 11 indicated that they could bind to the active site of EGFR TK.

Background: Schiff bases are synthetically accessible compounds that have been used in medicinal chemistry. Methods & results: In this work, 27 Schiff bases derived from diaminomaleonitrile were synthesized in high yields (80-98%). Molecular docking studies suggested that the Schiff bases interact with the catalytic site of cruzain. The most active cruzain inhibitor, analog 13 (IC 50  = 263 nM), was predicted to form an additional hydrophobic contact with Met68 in the binding site of the enzyme. A strong correlation between the IC 50 values and ChemScore binding energies was observed (R = 0.99). Kernel-based 2D quantitative structure-activity relationship models for the whole dataset yielded sound correlation coefficients (R 2  = 0.844; Q 2  = 0.719). Conclusion: These novel and potent cruzain inhibitors are worthwhile starting points in further Chagas disease drug discovery programs.

6-Thienylpyrimidine-5-carbonitrile derivatives were synthesized and screened for their in vitro antiproliferative activities against two human breast cancer cell lines in comparison to 5-fluorouracil as a reference. Compounds 2, 3a-c, and 6b evolved as the most active congeners against both cell lines, while others showed selectivity for only one cell line. Compound 2 exerted its effect through inhibition of the epidermal growth factor receptor (EGFR), while 6b showed less aromatase inhibitory activity than letrozole. The rest of the tested compounds did not show significant inhibition, and it can be assumed that they exert their antiproliferative activity through different target mechanisms. In addition, caspase-9 protein activation assays, cell cycle analysis using flow cytometry, and annexin V-fluorescein isothiocyanate-propidium iodide (FITC/PI) dual staining assays were performed for the most active compounds. All the tested compounds were found to be potent pyrimidine derivatives able to initiate apoptosis in MCF-7 and MDA-MB-231 cells., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Aromatic scaffolds are an important part of biologically active compounds and molecular probes used to study biochemical pathways and the involved targeted proteins of interest. 1-Oxo-1H-phenalene-2,3-dicarbonitrile-based compounds have been described as inhibitors of the BCL-2 family of proteins, and this core structure represents numerous possibilities for modifications that could lead to improved inhibitory potencies. Many studies demonstrated intriguing characteristics of these compounds in terms of reactivity and, interestingly, some contradictory literature reports appeared about reaction outcomes to synthesize them. Here, we initially provide a condensed overview of transformations performed on the phenalene scaffold, followed by the resynthesis of a 6-phenoxy-substituted derivative. We show that the initial determination of this particular structure was wrong and provide two-dimensional nuclear magnetic resonance (NMR) evidence to assign the structure properly. When preparing new derivatives using the same synthetic route, we observed 6- and 7-substituted regioisomers. After confirming their structures by NMR experiments, the ability of these compounds to inhibit BCL-2 was evaluated. The most potent 1-oxo-1H-phenalene-2,3-dicarbonitrile derivatives inhibited BCL-2 in the nanomolar range and showed double-digit micromolar cytotoxicity against four different cancer cell lines., (© 2021 The Authors. Archiv der Pharmazie published by Wiley-VCH Verlag GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

A solvent-assisted ESIPT fluorescent dye was synthesized and used as a probe (2-PPN) for the detection of F - /Ag + and high-resolution imaging of the cilia in live cells. The developed ESIPT fluorophore exhibited strong tautomeric fluorescence in protic solvents and normal emission in aprotic solvents, which is a significant departure from that of conventional intramolecular ESIPT compounds. The H-binding interaction of F - and the chelation of Ag + with the ESIPT module of 2-PPN resulted in significant tautomeric emission quenching. From this basis, the 2-PPN-based assays for the detection of F - and Ag + were established. The detection limit for F - and Ag + sensing is 2.4 nM and 1.5 nM, respectively. The selective experimental results showed that no tautomeric fluorescence change of 2-PPN could be observed in the presence of the other inorganic ions in the same medium, revealing high selectivity of 2-PPN to F - and Ag + . Furthermore, MTT assay experiments proved that the probe 2-PPN exhibited low cytotoxicity and good cell membrane permeability. The probe was also further successfully utilized to image the cilia in vitro MCF7 cells, displaying its high-resolution imaging performance.Graphical abstract., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Nitriles comprise a broad group of chemicals that are currently being industrially produced and used in fine chemicals and pharmaceuticals, as well as in bulk applications, polymer chemistry, solvents, etc. Aldoxime dehydratases catalyze the cyanide-free synthesis of nitriles starting from aldoximes under mild conditions, holding potential to become sustainable alternatives for industrial processes. Different aldoxime dehydratases accept a broad range of aldoximes with impressive high substrate loadings of up to >1 Kg L -1 and can efficiently catalyze the reaction in aqueous media as well as in non-aqueous systems, such as organic solvents and solvent-free (neat substrates). This paper provides an overview of the recent developments in this field with emphasis on strategies that may be of relevance for industry and sustainability. When possible, potential links to biorefineries and to the use of biogenic raw materials are discussed.

A highly efficient, direct C(sp 3 )-H cyanation was developed under mild photocatalytic conditions. The method enabled the direct cyanation of various C(sp 3 )-H substrates with excellent functional group tolerance. Notably, complex natural products and bioactive compounds were efficiently cyanated.

We report the use of 3-substituted 2-isocyanopyridines as convertible isocyanides in Ugi four-component reactions. The N-(3-substituted pyridin-2-yl)amide Ugi products can be cleaved by amines, alcohols, and water with Zn(OAc)2 as a catalyst. In addition, the applicability of the method was demonstrated in constrained di-/tripeptides bearing acid and base sensitive protective groups obtained via Ugi-4CR post-condensation modifications.

Designing of eco-friendly, low cost, and thermally stable stabilizing/supporting agents are always desired for production of catalyst systems which provide good catalytic performance in organic reactions. In this study, a novel, green, and efficient stabilizer containing chitosan/Co 3 O 4 microspheres (CS/Co 3 O 4 ) was developed. Palladium nanoparticles (Pd NPs) were then successfully immobilized on CS/Co 3 O 4 as a heterogeneous nanocatalyst (Pd NPs/CS/Co 3 O 4 ). Characterization of the designed materials were performed by FT-IR, TEM, FE-SEM, XRD, and EDS and it was determined that Pd NPs formed as approximately 20 nm. Catalytic behavior of Pd NPs/CS/Co 3 O 4 was investigated in the production of different substituted benzonitriles via aryl halide cyanation. Catalytic studies indicate that electron-rich or poor aromatic halides were smoothly cyanated with good reaction yields by Pd NPs/CS/Co 3 O 4 nanocatalyst by using K 4 [Fe(CN) 6 ] as the cyanating agent. Moreover, it was found that Pd NPs/CS/Co 3 O 4 nanocatalyst provided not only good reaction yields and but also good recovery/reusability for six times in the aryl halide cyanations. This paper displays that Pd NPs/CS/Co 3 O 4 nanocatalyst has a great catalytic and recycling potential for aryl halide cyanations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Solar radiation is the principal source of energy available to Earth and has unmatched potential for the synthesis of organic material from primordial molecular building blocks. As well as providing the energy for photochemical synthesis of (proto)biomolecules of interest in origins of life-related research, light has also been found to often provide remarkable selectivity in these processes, for molecules that function in extant biology and against those that do not. As such, light is heavily implicated as an environmental input on the nascent Earth that was important for the emergence of complex yet selective chemical systems underpinning life. Reactivity and selectivity in photochemical prebiotic synthesis are discussed, as are their implications for origins of life scenarios and their plausibility, and the future directions of this research.

Selective androgen receptor (AR) modulators (SARMs) are potent anabolic agents with a high potential of misuse in horseracing and equestrian sports. In this study, we applied label-free proteomics to discover plasma protein biomarkers in geldings (castrated horses) after administration with a popular SARM named RAD140. Tryptic peptides were prepared from plasma samples and analyzed by nano-flow ultrahigh-performance liquid chromatography-high-resolution tandem mass spectrometry (nano-UHPLC-HRMS/MS) using data-independent acquisition (DIA) method. Orthogonal projection on latent structure-discriminant analysis (OPLS-DA) has led to the development of a predictive model that could discriminate RAD140-administered samples from control samples and could also correctly classify 18 out of 19 in-training horses as control samples. The model comprises 75 proteins with variable importance in projection (VIP) score above 1. Gene Ontology (GO) enrichment analysis and literature review have identified upregulation of AR-regulated clusterin, and proteins associated with inflammation (haptoglobin, cluster of differentiation 14 [CD14], and inter-alpha-trypsin inhibitor heavy chain 4 [ITIH4]) and erythropoiesis (glycosylphosphatidylinositol-specific phospholipase D1 [GPLD1]) after RAD140 administration. Their changes were confirmed by selected reaction monitoring (SRM) experiments. Similar effects have been reported by the use of androgens and other SARMs. This is the first reported study that describes the use of a proteomic biomarker approach to detect horses that have been administered with RAD140 by applying label-free proteomic profiling of plasma samples. These results support the concept of a biomarker-driven approach to enhance the doping control of RAD140 and potentially other SARMs in the future., (© 2020 John Wiley & Sons, Ltd.)

A simple, efficient, and transition metal-free approach to synthesize functionalized 2-(alkynyl)benzonitriles has been developed using suitably functionalized 2H-pyran-2-ones and 4-phenyl/trimethylsilanyl-but-3-yn-2-ones as precursors. The reaction proceeds in the presence of a base at room temperature to yield internal as well as terminal alkynes. The structure of the synthesized compound was confirmed by single-crystal X-ray analysis. The molecular docking study was performed to evaluate the binding mode of action of newly synthesized alkyne derivatives with known human breast cancer target receptor aromatase (PDB ID: 3EQM).

Pyroptosis as a lytic and inflammatory form of cell death is a powerful tool to fight against cancer. However, pyroptosis is usually activated by chemotherapeutic drugs, which limits its anti-tumor applications due to drug resistance and severe side effects. Herein, we demonstrate that membrane targeting photosensitizers can induce pyroptosis for cancer cell ablation with noninvasiveness and low side effects. A series of membrane anchoring photosensitizers (TBD-R PSs) with aggregation-induced emission (AIE) characteristics were prepared through conjugation of TBD and phenyl ring with cationic chains. Upon light irradiation, cytotoxic ROS were produced in situ, resulting in direct membrane damage and superior cancer cell ablation. Detailed study revealed that pyroptosis gradually became the dominant cell death pathway along with the increase of TBD-R PSs membrane anchoring capability. This study offers a photo-activated pyroptosis-based intervention strategy for cancer cell ablation., (© 2021 Wiley-VCH GmbH.)

The conversion of an aldehyde into a nitrile can be efficiently performed using O-phenylhydroxylamine hydrochloride in buffered aqueous solutions. The reported method is specifically optimized for aqueous-soluble substrates including carbohydrates. Several reducing sugars including monosaccharides, disaccharides, and silyl-protected saccharides were transformed into cyanohydrins in high yields. The reaction conditions are also suitable for the formation of nitriles from various types of hydrophobic aldehyde substrates. Furthermore, cyanide can be eliminated from cyanohydrins, analogous to the Wohl degradation, by utilizing a readily-removed weakly basic resin as a promoter., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. 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 IC 50  = 9.09 - 31.11 µM compared to the positive controls: bicalutamide (IC 50  = 45.20 -51.61 µM) and enzalutamide (IC 50  = 11.47 - 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15-30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH 2 ) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Optical imaging in the second near-infrared (NIR-II) windows reduces much more autofluorescence and photon scattering from biological tissues and allows further tissue penetration depth and superior spatial resolution in living bodies. Herein, a fused-ring 2,2'-((2Z,2'Z)-((12,13- bis (2-ethylhexyl)-3,9-diundecyl-12,13-dihydro-[1,2,5]thiadiazolo[3,4-e]thieno[2,″3″:4',5']thieno[2',3':4,5]pyrrolo[3,2-g]thieno[2',3':4,5]thieno[3,2- b ]indole-2,10-diyl)bis(methanylylidene)) bis (5,6-difluoro-3-oxo-2,3-dihydro-1 H -indene-2,1-diylidene))dimalononitrile (TPBT) molecule was explored as a multifunctional tumor theranostic reagent for photothermal/photodynamic therapy guided by NIR-II imaging. The TPBT molecule has an electron-deficient core with a ladder-type multi-fused ring and shows a narrow band gap that can enhance the near-infrared absorption. The J -aggregative TPBT NPs were formed by nanoprecipitation with great bathochromic shift in absorption and emission spectra, which endows them with ideal fluorescence imaging ability in the NIR-II region. Moreover, TPBT NPs present both higher photothermal conversion efficiency (∼36.5%) and effective ROS generation ability, making them excellent candidate for cancer photothermal/photodynamic therapy. Moreover, the biocompatible TPBT NPs can effectively passively target tumor sites due to their enhanced permeability and retention effect for more precision treatment. Thus, TPBT NPs as a multifunctional phototheranostic agent in the NIR-II region present promising potential in clinical cancer NIR-II imaging-guided phototherapy.

The two isotopomers of teriflunomide were synthesized starting from isotopically stable-labeled stocks of [ 13 C]potassium cyanide and [1- 13 C]ethyl bromoacetate. The two 13 C-labeled compounds 1a, b were applied in several NMR studies to study the E/Z ratio in different matrices. In a solution, such as dimethyl sulfoxide (DMSO), a dynamic equilibrium between E/Z-isomers (ratio of 8:92) was determined by initial 13 C-carbon NMR experiments. To get insights into the E/Z ratio of teriflunomide under in vivo conditions, advanced heteronuclear NMR (heteronuclear Overhauser effect spectroscopy [HOESY]) in D 2 O and mixtures of D 2 O/plasma were performed. Whereas NMR experiments in mixtures of water and plasma failed owing to extreme line broadening, NMR spectra in water at pH 7.4 showed only the Z-isomer., (© 2020 John Wiley & Sons, Ltd.)

A bioisosteric carboxamide - sulfonamide replacement explored during the optimization of an insecticide lead compound led to the surprising discovery of a formerly unknown subclass of the Carboxylic Acid Amide (CAA) fungicides, which is the very first CAA fungicide group without a carboxamide function. In this paper we present invention pathway, racemic and stereoselective synthesis routes, structure-activity relationship studies as well as resistance profile of this novel family of fungicides., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: Compounds that block enzyme activity can kill pathogens and help develop effective and safe drugs for Chagas disease and leishmaniasis. Materials & methods: A library of nonpeptidic nitrile-based compounds was synthesized and had their inhibitory affinity tested against cruzain, Leishmania mexicana cysteine protease B and cathepsin L. Isothermal titration calorimetry experiments and molecular simulations were performed for selected compounds to obtain thermodynamic fingerprints and identify main interactions and putative modes of binding with cruzain. Results: The derivatives provided increased affinity against all enzymes compared with the lead, and thermodynamic and computational studies showed improved thermodynamic properties and a possible different mode of binding. Conclusion: Our studies culminated in 1b, a compound 60-fold more potent in cruzain than its lead that also showed entropic and enthalpic contributions favorable to Gibbs binding energy.

Aim and Objective: In this work, we tried to introduce a non-toxic and stable organic compound named succinimide as a green and efficient organo-catalyst for the promotion of the synthesis of arylidene malononitrile and tetrahydrobenzo[b]pyran derivatives. Using this method led to a clean procedure to achieve these types of bioactive compounds without a specific purification step. The rate and yield of the reactions were excellent, and also succinimide showed acceptable reusability as the catalyst., Materials and Methods: In a 25 mL round-bottom flask, [A: a mixture of aromatic aldehyde (1 mmol), malononitrile (1.1 mmol) and B: a mixture of aromatic aldehyde (1.0 mmol), malononitrile (1.1 mmol)] and succinimide (0.2 mmol) in H2O/ EtOH [5 mL (1:1)] was stirred at 80 °C for an appropriate time. After completion of the reaction, which was monitored by TLC [n-hexane-EtOAc (7:3)], the mixture was cooled to room temperature, and the solid product was filtered, washed several times with cold distilled water to obtain the corresponding pure product., Results: After the optimization of the conditions and amount of the catalyst, a series of aromatic aldehydes containing either-electron-donating or electron-withdrawing substituents were successfully used for both of the reactions. The reactions rates and yields under the selected conditions were excellent. The nature and electronic properties of the substituents had no obvious effect on the rate and yield of the reaction. Meanwhile, the catalyst showed acceptable reusability for these two reactions., Conclusion: In this work, we have introduced Succinimide as a green and safe organo-catalyst for the efficient synthesis arylidene malononitrile and tetrahydrobenzo[b]pyran derivatives. The results showed that the catalyst had excellent efficiency in green aqueous media and also the reusability of the catalyst was good., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Functionalized carbon nitride quantum dots (CNQDs) are fabricated by moderate carbonization of L-tartaric acid and urea in oil acid media by a facile microwave-assisted solvothermal method. The obtained CNQDs are monodispersed with a narrow size distribution (average size of 3.5 nm), and exhibit excellent selectivity and sensitivity of fluorescence quenching for 2,4,6-trinitrophenol (TNP) with a quenching efficiency coefficient K sv of 4.75 × 10 4  M -1 . This sensing system exhibits a fast response time within 1 min and a wide linear response range from 0.1 to 15 μM. The limit of detection is as low as 87 nM, which is comparable or lower than the other probes. The application of the developed probe to the detection of TNP in spiked water samples yields satisfactory results. The mechanism of fluorescence quenching is also discussed. Graphical Abstract An optical sensor based on functionalized carbon nitride quantum dots (CNQDs) were fabricated from L-tartaric acid and urea by a facile one-pot microwave-assisted solvothermal method, and were effectively utilized to the detection of 2,4,6-trinitrophenol (TNP) based on fluorescence (FL) quenching.

The pharmaceutical industry has to tackle the explosion of high amounts of poorly soluble APIs. This phenomenon leads to numerous sophisticated solutions. These include the use of multifactorial data analysis identifying correlations between the components and dosage form properties, laboratory and production process parameters with respect to the API liberation Example of such API is bicalutamide. Improved liberation is achieved by particle size reduction. Laboratory batches, with different PSD of API, were filled into gelatinous capsules and consequently granulated for tablet compression. Comparative dissolution profiles with Casodex 150 mg (Astra Zeneca) were performed. The component analysis was used for the statistical evaluation of f 1 and f 2 factors and D(v,0.9) and D[4,3] parameters of PSD to identify optimal PSD values. Suitable PSD limits for API were statistically confirmed in laboratory and in commercial scale with respect to optimized tablet properties. The tablets were bioequivalent with originator (n = 20; 90% CI for ln AUC 0-120 : 99.8-111.9%; 90% CI for ln c max : 101.1-112.9%). In conclusion, the micronisation of the API is still an efficient and inexpensive method improving the bioavailability, although there are more complicated and expensive methods available. Statistical multifactorial methods improved the safety and reproducibility of production.

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of 15 bicalutamide analogues (sulfide, deshydroxy, sulfone, and O -acetylated) were prepared and their antiproliferative activity evaluated against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP, and VCap). Bicalutamide and enzalutamide were used as positive controls. Seven of these compounds displayed remarkable enhancement in anticancer activity across the four PC cell lines. The deshydroxy analogue ( 16 ) was the most active compound with IC 50 = 6.59-10.86 µM. Molecular modeling offers a plausible explanation of the higher activity of the sulfide analogues compared to their sulfone counterparts.

Testing of an expanded, 800-compound set of analogues of the earlier described Strecker-type α-aminonitriles (selected from publicly available Enamine Ltd. Screening Collection) in thermal shift assay against bovine carbonic anhydrase ( b CA) led to further validation of this new class of inhibitors and identification a new, refined chemotype represented by inhibitors with 10-improved potency. [Formula: see text].

A zinc bromide-catalyzed synthesis of 5-substituted tetrazoles via DNA-conjugated nitriles using sodium azide has been developed. The protocol offered moderate to excellent yields of tetrazoles with a broad range of substrates, including a variety of functionalized aromatic, heterocyclic, and aliphatic nitriles. In addition, the electronic effect within the substrate scope was evaluated. DNA fidelity was assessed by ligation efficiency and amplifiability analysis. The ability to generate tetrazoles expands the diversity of heterocycles in the preparation of DNA-encoded chemical libraries.

Leishmania mexicana is an obligate intracellular protozoan parasite that causes the cutaneous form of leishmaniasis affecting South America and Mexico. The cysteine protease LmCPB is essential for the virulence of the parasite and therefore, it is an appealing target for antiparasitic therapy. A library of nitrile-based cysteine protease inhibitors was screened against LmCPB to develop a treatment of cutaneous leishmaniasis. Several compounds are sufficiently high-affinity LmCPB inhibitors to serve both as starting points for drug discovery projects and as probes for target validation. A 1.4 Å X ray crystal structure, the first to be reported for LmCPB, was determined for the complex of this enzyme covalently bound to an azadipeptide nitrile ligand. Mapping the structure-activity relationships for LmCPB inhibition revealed superadditive effects for two pairs of structural transformations. Therefore, this work advances our understanding of azadipeptidyl and dipeptidyl nitrile structure-activity relationships for LmCPB structure-based inhibitor design. We also tested the same series of inhibitors on related cysteine proteases cathepsin L and Trypanosoma cruzi cruzain. The modulation of these mammalian and protozoan proteases represents a new framework for targeting papain-like cysteine proteases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In this article, we describe the synthesis of 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides bearing cyclic diamine residues at positions 6 or 7; the synthesis is based on the nucleophilic substitution of halogens. All synthesized 6(7)-aminoquinoxaline-2-carbonitrile 1,4-dioxides 3-6 demonstrated higher cytotoxicity and hypoxia selectivity compared to the reference agent tirapazamine against breast adenocarcinoma cell lines (MCF7, MDA-MB-231). The structure and position of the diamine residue considerably affects the antiproliferative properties of the quinoxaline-2-carbonitrile 1,4-dioxides. The introduction of a halogen atom at position 7 in the quinoxaline ring of 4a considerably increases the cytotoxicity of compounds 5a and 6a under both normoxic and hypoxic conditions. However, the most hypoxia-selective derivatives were non-halogenated 7-aminosubstituted 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides 3a-j. Of the 32 novel synthesized derivatives, approximately 20 of the 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides demonstrated high antiproliferative potency against wild type leukemia cells K562 and drug-resistant subline K562/4 with the expression of p-glycoprotein (p-gp) compared to the reference agent doxorubicin, which exhibited one order of magnitude lower activity towards K562/4 cells than towards K562 cells. Lead compounds 5a and 3f inhibited HIF-1α expression and activity and induced apoptosis in hypoxic tumor cells, which was confirmed by poly(ADP-ribose)polymerase (PARP) cleavage. Moreover, 5a and 3f showed strong antiestrogenic potencies in MCF7 breast cancer cells. Thus, the described series of quinoxaline 1,4-dioxides has high anticancer potential and good aqueous solubility. Therefore, these compounds are promising for further drug development of hypoxia-targeted anticancer agents., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The enzymatic family of heme oxygenase (HO) is accountable for heme breakdown. Among the two isoforms characterized to date, HO-2 is poorly investigated due to the lack of potent HO-2 chemical modulators and the greater attentiveness towards HO-1 isoform. In the present paper, we report the rational design and synthesis of HO-2 inhibitors achieved by modulating the volume of known HO-1 inhibitors. The inhibition preference has been moved from HO-1 to HO-2 by merely increasing the volume of the substituent in the western region of the inhibitors. Docking studies demonstrated that new derivatives soak differently in the two binding pockets, probably due to the presence of a Tyr187 residue in HO-2. These findings could be useful for the design of new selective HO-2 compounds., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). These compounds were synthesized and evaluated for their in vitro cytotoxic activities against a panel of four human tumor cell lines, namely colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and non-small cell lung cancer cells (A549). Five of the synthesized compounds, 11a, 11b, 12b, 15b and 16a, were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib. In particular, compound 11b showed 4.5- to 8.4-fold erlotinib activity against HCT-116, HepG-2, MCF-7, and A549 cells with IC50 values of 3.37, 3.04, 4.14, and 2.4 μM respectively. Moreover, the most cytotoxic compounds that showed promising IC50 values against the four cancer cell lines were subjected to further investigation for their kinase inhibitory activities against EGFRWT and EGFRT790M using homogeneous time resolved fluorescence (HTRF) assay. Compound 11b was also found to be the most active compound against both EGFRWT and mutant EGFRT790M, exhibiting IC50 values of 0.09 and 4.03 μM, respectively. The cell cycle and apoptosis analyses revealed that compound 11b can arrest the cell cycle at the G2/M phase and induce significant apoptotic effects in HCT-116, HepG-2, and MCF-7 cells. Additionally, compound 11b upregulated the level of caspase-3 by 6.5 fold in HepG-2 when compared with the control. Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFRWT and EGFRT790M. Additional in silico ADMET studies were performed to explore drug-likeness properties.

Malaria is a prevalent and deadly disease. The fast emergence of drug-resistant malaria parasites makes the situation even worse. Thus, developing new chemical entities, preferably with novel mechanisms of action, is urgent and important. Inspired by the complex and scarce isonitrile-containing terpene natural products, we evaluated a collection of easily prepared synthetic mono- and bis-isonitrile compounds, most of which feature a simple, but rigid stilbene backbone. From this collection, potent antimalarial lead compounds with EC 50 value ranging from 27 to 88 nM against the Dd2 strain using a blood stage proliferation assay were identified. Preliminary SAR information showed that the isonitrile group is essential for the observed activity against the Dd2 strain and the bis-isonitrile compounds in general perform better than the corresponding mono-isonitrile compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A novel set of 2-cyanoacrylamides linked to ethyl 1,3-diphenylpyrazole-4-carboxylates moiety were synthesized and elucidated by different spectroscopic tools. In vitro cytotoxic assay was carried out against different cell lines (Hct 116 , A 549 , MDA-MB 231 , and HFB 4 ). Ethyl 5-(2-cyano-3-(furan-2-yl)acrylamido)-1,3-diphenylpyrazole-4-carboxylate 5 achieved the potent cytotoxic effect toward all tested cancer cell lines especially colon cancer (HCT 116 ) with IC 50 value (30.6 µg/ml) relative to the lead compound 3 and the standard positive control 5-FU. Additionally, it exhibited less toxic effect toward the normal human melanocytes (HFB4) cell line. Compound 5 was theoretically investigated and compared for its binding affinity to a model of protein markers relative to the lead compound 3 using two different molecular docking programs. More investigations were performed in an attempt to find out the molecular mechanism of this novel compound inside colon cancer cells, as real time PCR analysis, Elisa assay, flow cytometry, and morphological characterizations using TEM and SEM tools.Herein, we showed that compound 5 interferes with the intrinsic pathway of apoptosis at the mitochondrial level in response to an apoptogenic stimulus as cytochromec, caspase-9 and caspases-3 which were triggered by our novel compound 5. All molecular investigations proved that intrinsic apoptotic pathway of colorectal carcinoma was strongly initiated by the effect of compound 5 through upregulation of mitochondrial apoptosis related genes as (Caspase-3, caspase-9, BAX, P 53 , and cytochrome-c) and down-regulated anti-apoptotic proteins (BCL2, MMP1, CDK4, and VEGFR). Further studies proved cell cycle arrest of HCT 116 cell lines at G2/M phase after treatment. In addition, our data revealed that our novel efficiently damage the genomic DNA of colorectal cells involving P 53 dependent mechanism using DPA assay. Sever morphological and ultrastructural changes were detected in colorectal cells treated by compound 5 compared to control using both scanning electron microscopy (SEM) and transmission electron microscopy (TEM)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We report a biocompatible and rapid reaction between cysteine thiols and 2,4-difluoro-6-hydroxy-1,3,5-benzenetricarbonitrile (DFB), which enables the efficient cyclization of peptides in neutral aqueous solutions. The reaction was further applied to cyclize peptides displayed on the phage surface without reducing phage infectivity, thus affording high-quality cyclic peptide libraries useful for screening of cyclic peptide ligands. Using the DFB-cyclic peptide library, we identified ligands that can distinguish the pro-survival protein Bcl-xl from its close relative Bcl-2. Therefore, this study on one hand reports a useful reaction for the construction of cyclic peptide libraries, and on the other hand presents valuable hits for further design of selective Bcl-xl ligands.