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Over the past years, the poultry industry has been assigned to greater production performance but has become highly sensitive to environmental changes. The average world temperature has recently risen and is predicted to continue rising. In open-sided houses, poultry species confront high outside temperatures, which cause heat stress (HS) problems. Cellular responses are vital in poultry, as they may lead to identifying confirmed HS biomarkers. Heat shock proteins (HSP) are highly preserved protein families that play a significant role in cell function and cytoprotection against various stressors, including HS. The optimal response in which the cell survives the HS elevates HSP levels that prevent cellular proteins from damage caused by HS. The HSP have chaperonic action to ensure that stress-denatured proteins are folded, unfolded, and refolded. The HSP70 and HSP90 are the primary HSP in poultry with a defensive function during HS. HSP70 was the optimal biological marker for assessing HS among the HSP studied. The current review attempts to ascertain the value of HSP as a heat stress defense mechanism in poultry. [ABSTRACT FROM AUTHOR]

Protein kinases are promising therapeutic targets for cancer therapy. Here, we applied multiple approaches to optimize the potency and selectivity of our reported alloxazine scaffold. Flexible moieties at position 2 of the hetero-tricyclic system were incorporated to fit into the ATP binding site and extend to the adjacent allosteric site and selectively inhibit protein kinases. This design led to potential selective inhibition of ABL1, CDK1/Cyclin A1, FAK, and SRC kinase by 30–59%. Cytotoxicity was improved by ∼50 times for the optimized lead ( 10b ; IC 50  = 40 nM) against breast cancer (MCF-7) cells. Many compounds revealed potential cytotoxicity against ovarian (A2780) and colon carcinoma (HCT116) cells of ∼10–30 time improvement (IC 50 5–17 nM). The results of the Annexin-V/PI apoptotic assay demonstrated that many compounds induced significantly early (89–146%) and a dramatically late (556–1180%) cell death in comparison to the vehicle control of MCF-7 cells. SAR indicated that 5-deazaalloxazines have a higher selectivity for Abl-1 and FAK kinases than alloxazines. The correlations between GoldScore fitness into FAK and SRC kinases and IC 50 against MCF-7 and A2780 cells were considerable (R 2 : 0.86–0.98). [ABSTRACT FROM AUTHOR]

Two novel series including Schiff bases of the pyrrolizine-5-carboxamides and their Cu(II) complexes were designed, synthesized and analysed using spectral and analytical techniques. The analytical results indicated the formation of the complexes in 1:1 or 1:2 (Metal:Ligand) ratio. The geometry around the Cu centers was confirmed to be tetrahedral or octahedral. The cytotoxic activity of the new compounds was evaluated using MCF-7 (human breast adenocarcinoma), A2780 (human ovary adenocarcinoma) and HT29 (human colon adenocarcinoma), in addition to MRC5 (normal human fetal lung fibroblast) cells using the MTT cytotoxicity assay. The Schiff base 12c and the Cu complex 13b were the most active in the two series with IC 50 values in the range of 0.14–2.54 μM against the three cell lines. Also, the Cu complex 13e showed excellent activity against HT29 with IC 50  = 0.05μM. 7-Cyano- N -(4-methoxyphenyl)-6-((3-phenylallylidene) amino)-2,3-dihydro-1 H -pyrrolizine-5-carboxamide (12c) showed high selectivity (6–13 folds) for cancerous cells over normal cells; and it induced marginal increases in the G1 and S phases of MCF-7 cells during cell cycle analysis, while compound 13b increased the MCF-7 Sub-G1 proapoptotic population, and blocked cells in the G2-M phase in a dose dependent manner. The annexin V apoptosis assay revealed the ability of compounds 12c and 13b to increase the early apoptotic MCF-7 cell populations two and three fold, respectively. Furthermore, these findings were supported by data showing that the two compounds ( 12c and 13b ) elicit cytotoxic activity. Taken together, the data presented in this study warrants further in vitro and in vivo investigations. [ABSTRACT FROM AUTHOR]

A novel set of pyrrolizine-5-carboxamides has been synthesized and evaluated for their anticancer potential against human breast MCF-7, lung carcinoma A549 and hepatoma Hep3B cancer cell lines. Compound 10c was the most active against MCF-7 with IC 50 value of 4.72 µM, while compound 12b was the most active against A549 and Hep3B cell lines. Moreover, kinases/COXs inhibition and apoptosis induction were suggested as potential molecular mechanisms for the anticancer activity of the novel pyrrolizines based on their structural features. The new compounds significantly inhibited COX-1 and COX-2 with IC 50 values in the ranges of 5.78–11.96 µM and 0.1–0.78 µM, respectively with high COX-2 selectivity over COX-1. Interestingly, the most potent compound in MTT assay, compound 12b , exhibited high inhibitory activity against COX-2 with selectivity index (COX-1/COX-2) > 100. Meanwhile, compound 12b displayed weak to moderate inhibition of six kinases with inhibition% (7–20%) compared to imatinib (inhibition% = 1–38%). The results of cell cycle analysis, annexin V PI/FITC apoptosis assay and caspase-3/7 assay revealed that compound 12b has the ability to induce apoptosis. The docking results of compound 12b into the active sites of COXs, ALK1 and Aurora kinases indicated that it fits nicely inside their active sites. Overall, the current study highlighted the significant anticancer activity of the newly synthesized pyrrolizines with a potential multi-targeted mechanism which could serve as a base for future studies and further structural optimization into potential anticancer agents. [ABSTRACT FROM AUTHOR]

Despite the existence of huge number of NSAIDs, the quest for safer drugs is still in the focus of several drug discovery programs. Pyrrolizine heterocyclic system is among the privileged scaffolds utilized in this regard. At least one of these pyrrolizines, ketorolac, has reached the market. The current review represents a collective effort to highlight the reported pyrrolizines with anti-inflammatory and analgesic potential and categorize them into eight different classes. Furthermore, the various synthetic approaches, structure-activity relationship as well as metabolic pathways have been discussed. Taken together, this review sets a base for researchers to design and synthesize novel pyrrolizine-based libraries for further development into safer and efficient anti-inflammatory and analgesic agents. [ABSTRACT FROM AUTHOR]

In this investigation, full-scale reinforced-concrete (RC) circular-beams with glass fibre reinforcement polymer (GFRP) bars and spirals were modeled using nonlinear finite element (FE) program. All the specimens had 3000-mm length. The RC-beams were modeled in a three-dimension space, taking into account the material nonlinearity and the elastic plastic behavior of the concrete, in addition to the elastic characteristics of the GFRP materials. The results of the numerical analysis were verified by comparing them against experimental results of six similar previously tested specimens, that had 500-mm diameter. The analysis included tracing the load-deformation response of the RC circular-beams, load-strains behavior on the surface of the concrete as well as the strains in the GFRP bars. The outputs from the FE analysis showed that the program was able to foresee the experimental results with good precision. The, average, value for the experimental shear strength to the foreseen ones by the FE program, (V exp /V Model) for the six beams, is "1.00 ± 0.05″ with 2.5% COV. After ward, a parametric study was performed to expand and evaluate more parameters such as size effect (200, 300, and 400 mm), span-to-depth (a/d) ratio from 1.5 to 3.5, and spirals' reinforcement ratio between 0.32 and 1.27%. The numerical investigation confirmed the prominent effect of these parameters on the shear strength and behavior of the GFRP-RC circular-beams. [ABSTRACT FROM AUTHOR]

Since 2020, many compounds have been investigated for their potential use in the treatment of SARS-CoV-2 infection. Among these agents, a huge number of natural products and FDA-approved drugs have been evaluated as potential therapeutics for SARS-CoV-2 using virtual screening and docking studies. However, the identification of the molecular targets involved in viral replication led to the development of rationally designed anti-SARS-CoV-2 agents. Among these targets, the main protease (Mpro) is one of the key enzymes needed in the replication of the virus. The data gleaned from the crystal structures of SARS-CoV-2 Mpro complexes with small-molecule covalent inhibitors has been used in the design and discovery of many highly potent and broad-spectrum Mpro inhibitors. The current review focuses mainly on the covalent type of SARS-CoV-2 Mpro inhibitors. The design, chemistry, and classification of these inhibitors were also in focus. The biological activity of these inhibitors, including their inhibitory activities against Mpro, their antiviral activities, and the SAR studies, were discussed. The review also describes the potential mechanism of the interaction between these inhibitors and the catalytic Cys145 residue in Mpro. Moreover, the binding modes and key binding interactions of these covalent inhibitors were also illustrated. The covalent inhibitors discussed in this review were of diverse chemical nature and origin. Their antiviral activity was mediated mainly by the inhibition of SARS-CoV-2 Mpro, with IC 50 values in the micromolar to the nanomolar range. Many of these inhibitors exhibited broad-spectrum inhibitory activity against the Mpro enzymes of other coronaviruses (SARS-CoV-1 and MERS-CoV). The dual inhibition of the Mpro and PLpro enzymes of SARS-CoV-2 could also provide higher therapeutic benefits than Mpro inhibition. Despite the approval of nirmatrelvir by the FDA, many mutations in the Mpro enzyme of SARS-CoV-2 have been reported. Although some of these mutations did not affect the potency of nirmatrelvir, there is an urgent need to develop a second generation of Mpro inhibitors. We hope that the data summarized in this review could help researchers in the design of a new potent generation of SARS-CoV-2 Mpro inhibitors. [Display omitted] • The classification of the covalent inhibitors of SARS-CoV-2 Mpro was discussed. • The design and/or identification strategies were summarized. • Their antiviral activity, Mpro inhibitory activity, and SAR were described. • The potential mechanisms of the interaction with Cys145 were presented. • The binding modes and interactions of selected inhibitors with Mpro were provided. [ABSTRACT FROM AUTHOR]

Several studies have indicated the potential therapeutic outcomes of combining selective COX-2 inhibitors with tubulin-targeting anticancer agents. In the current study, a novel series of thiazolidin-4-one-based derivatives (7a–q) was designed by merging the pharmacophoric features of some COXs inhibitors and tubulin polymerization inhibitors. Compounds 7a–q were synthesized and evaluated for their cytotoxic activity against MCF7, HT29, and A2780 cancer cell lines (IC 50 = 0.02–17.02 μM). The cytotoxicity of 7a–q was also assessed against normal MRC5 cells (IC 50 = 0.47–13.46 μM). Compounds 7c , 7i , and 7j , the most active in the MTT assay, significantly reduced the number of HT29 colonies compared to the control. Compounds 7c , 7i , and 7j also induced significant decreases in the tumor volumes and masses in Ehrlich solid carcinoma-bearing mice compared to the control. The three compounds also exhibited significant anti-HT29 migration activity in the wound-healing assay. They have also induced cell cycle arrest in HT29 cells at the S and G 2 /M phases. In addition, they induced significant increases in both early and late apoptotic events in HT29 cells compared to the control, where 7j showed the highest effect. On the other hand, compound 7j (1 μM) displayed weak inhibitory activity against tubulin polymerization compared to colchicine (3 μM). On the other hand, compounds 7a – q inhibited the activity of COX-2 (IC 50 = 0.42–29.11 μM) compared to celecoxib (IC 50 = 0.86 μM). In addition, 7c , 7i , and 7j showed moderate inhibition of inflammation in rats compared to indomethacin, with better GIT safety profiles. Molecular docking analysis revealed that 7c , 7i , and 7j have higher binding free energies towards COX-2 than COX-1. These above results suggested that 7j could serve as a potential anticancer drug candidate. [Display omitted] • A novel series of thiazolidin-4-one derivatives (7a–q) was reported with potent and selective cytotoxicity to HT29 cells. • The most active compounds, 7c , 7i , and 7j , reduced the number of HT29 colonies, suppressed the migration of HT29 cells, and decreased tumor volumes and masses in ESC-bearing mice compared to the control. • The three compounds induced apoptosis and cell cycle arrest in HT29 cells. • Compared with indomethacin, these compounds showed moderate anti-inflammatory activity and superior GIT safety. • Among these derivatives, 7j exhibited the highest binding free energies towards tubulin and COX-2 proteins. [ABSTRACT FROM AUTHOR]

Using a repurposing approach, a series of previously reported antiproliferative indole-based carboxamides (9 – 23) were reassessed for their anti-SARS-CoV-2 viral activity as main protease (SARS-CoV-2 Mpro) inhibitors. The structure of the indole-based carboxamides was validated by comparing the acquired data to previously report physicochemical and NMR spectroscopy data. The anti-SARS-CoV-2 activity of the synthesised compounds was tested in Vero-E6 cells using SARS-CoV-2 (NRC-03-nhCoV) virus. MTT cytotoxicity assay results demonstrated that compounds 9–23 had CC 50 (50% cytotoxicity concentration) values ranging from 325.60 to 578.50 μM and safety indices ranging from 21.40 to 99.60. Most of the compounds examined significantly inhibited NRC-03-nhCoV virus replication, with IC 50 values ranging from 3.60 μM to 15.20 μM, with compounds 11 , 19 , and 20 having the most potent anti-SARS-COV-2 activity. The inhibitory effect of compounds 11, 13, 14, 19 and 20 against SARS-CoV-2 Mpro was investigated. The findings of this test were consistent with the anti-SARS CoV-2 experiment. Inflammatory cytokine tests revealed that compounds 11 , 19 and 20 have antiviral effectiveness against SARS-CoV-2 and can reduce hyper inflammation. Finally, docking studies of the novel compounds in the SARS CoV-2-Mpro active site revealed a good match. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Synthesis of several substituted pyrrolizines 10a–f, 11a–f, 13a–c, pyrimidopyrrolizines 14a–c, 15a–c, and pyrrolizinopyrimidoisoindoles 12a–c was discussed. The starting compounds 6-amino-7-cyano-N-(4-(un)substitutedphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamides 9a–c were reacted with different aldehydes, acid chlorides, and acid anhydrides to give the target compounds. The structures of the new compounds were characterized by spectral and elemental analyses. All compounds were tested for their anti-inflammatory activity using the carrageenan-induced rat paw oedema model and exhibited weak to good activities compared to ketorolac as the reference drug. Also, analgesic activity of selected compounds, which are the most active in the anti-inflammatory screening, was measured using the acetic acid-induced writhing model; revealing activities comparable to or higher than ketorolac. Ulcer indices for the most active compounds were calculated and some compounds showed no or minimal ulcerogenic effect compared to ketorolac. [Copyright &y& Elsevier]

Targeting P-glycoprotein (P-gp, ABCB1 transporter), which plays an essential role in multi-drug resistance (MDR) in cancers, with new cytotoxic agents is a promising strategy in cancer chemotherapy. In the current study, we report the synthesis of thirteen novel pyrimidopyrrolizine, pyrimidoindolizine, and diazepinopyrrolizine derivatives. The new compounds exhibited cytotoxic activities against MCF7, A2780 and HT29 cancer cell lines (IC 50 = 0.02–19.58 μM) and MRC5 (IC 50 = 0.17–20.57 μM). The six most active compounds (23b , 24a , b and , 31c-e) were evaluated for their MDR reversal activities in MCF7/ADR cells. Mechanistic study using real-time PCR revealed the ability of compound 31c to inhibit P-gp. In addition, compound 31c increased the accumulation of Rho123 inside MCF7/ADR cells in a dose-dependent manner compared to verapamil. Compound 31c arrested the cell cycle of MCF7 cells at the G 1 phase. Compound 31c also caused a significant dose-dependent increase of early and late apoptotic events. Molecular docking analysis revealed a high binding affinity for compound 31c toward P-gp. Like zosuquidar, compound 31c displayed one hydrogen bond and several hydrophobic interactions with amino acids in P-gp. These results indicated that compound 31c represents a potential anticancer candidate with MDR reversal activity. [Display omitted] • New pyrimidopyrrolizine/indolizine, and diazepinopyrrolizine derivatives were synthesized and evaluated for their cytotoxicity against MCF7, A2780, HT29 and MRC5 cells. • The MDR reversal activity of compounds 23b , 24a , b , 31c - e was investigated in MCF7/ADR cells. • Compounds 31c inhibited P-gp and increased the accumulation of Rho123 inside MCF7/ADR cells. • Compound 31c arrested cells at the G 1 cell cycle phase and induced apoptosis in MCF7 cells. • The potential binding mode of compound 31c into P-gp was investigated in a molecular docking study. [ABSTRACT FROM AUTHOR]

Two new series of pyrrolizine-5-carboxamides were synthesized and evaluated for their anticancer and anti-inflammatory activities. The new compounds exhibited potent cytotoxicity (IC 50 = 0.10–22.96 μM) against three cancer (MCF-7, A2780 and HT29) cell lines with selectivity index in the range of 1–258. Moreover, these compounds also exhibited significant anti-inflammatory activity (18.13–44.51% inhibition of inflammation) mediated by inhibition of COX-1/2 with preferential inhibition of COX-2. The study of SAR revealed favorable cytotoxic outcomes of the aliphatic side chain and 4-thiazolidinone moiety at C6 of the pyrrolizine nucleus, while anti-inflammatory activities was improved with the (hetero)aromatic substituents. The IC 50 values which inhibit COX-2 were higher than those needed to inhibit the growth of cancer cell lines. Mechanistic studies also revealed inhibition of multiple kinases by compounds 12 , 19 and 22. Moreover, compounds 12 , 14 , 16 and 22 induced cell cycle arrest and apoptosis in MCF-7 cells. Docking studies revealed nice fitting of the new compounds into COX-1/2. Additionally, compounds 12 , 19 and 22 also exhibited higher affinity for CDK2 than CAN508. To sum up, the above-mentioned data highlight these compounds as promising anti-inflammatory and anticancer agents. Image 1 • Two new series of pyrrolizines bearing Schiff bases or 4-thiazolidinone moiety were synthesized and evaluated for their cytotoxic activity. • Compound 22 induced G1 cell cycle arrest and apoptosis in MCF-7 cells. • Compounds 12 , 19 and 22 displayed inhibitory activity against CDK2 (IC 50 = 0.58–1.27 μM). • Compounds 14 exhibited potent in vivo anti-inflammatory activity mediated by COX-2 inhibition (IC 50 = 0.64 μM). • Binding modes of the new compounds into COXs, CDK2, Aurora A, BRAF and EGFR enzymes were investigated. [ABSTRACT FROM AUTHOR]