Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kß kinases.

Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds 5, 4b, and 4a possessed potent cytotoxic activity against PC-3 cells with IC50 3.56, 8.99, and 10.22 µM, respectively. Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC50 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC50 0.1812 µM, as well as PI3Kß inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kß inhibiting activity. Docking aligns with the in vitro results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.

Schiff bases as linker in the development of quinoline-sulfonamide hybrids as selective cancer-associated carbonic anhydrase isoforms IX/XII inhibitors: A new regioisomerism tactic.

A novel set of quinoline tailored with the sulfonamide as zinc-binding group (ZBG) has been rationalized and synthesized as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Such hybrids were decorated by a novel elongated imine linker with/without ethylene spacer with variable hydrophobic and lipophilic pockets. Therefore, a regioisomeric tactic has been established, most of which act as efficient inhibitors of the tumor-associated CA isoforms IX and XII. Interestingly, one hybrid 10b displayed an appreciable activity in MCF-7 cell line under normoxic condition (IC50 of 8.42 µM) in comparison to the standard staurosporine (IC50 = 5.34 µM) and excellent activity under hypoxic conditions (IC50 = 1.56 µM) in comparison to staurosporine (IC50 = 4.45 µM). Furthermore, hybrids 8a and 10b encouraged MCF-7 and MDA-MB-231 cell apoptosis alongside promising Bax/Bcl expression ratio change. Docking studies were also, performed and agreed with the biological results. Our SAR study suggested that our regiosiomerization tactic for the quinoline based-sulfonamide molecules led to effective inhibition of tumuor-relevant hCAs IX/XII.

Design and synthesis of uracil/thiouracil based quinoline scaffolds as topoisomerases I/II inhibitors for chemotherapy: A new hybrid navigator with DFT calculation.

In this work, a novel promising hybrid mode of uracil/thiouracil based quinoline pharmacophore i.e. 5a-f was rationalized and synthesized based on rigidification and lipophilic principles, and following the reported pharmacophoric features of camptothecin & doxorubicin. Concurrently, a non-rigid mode pharmacophore i.e. 7a-f was also designed and synthesized. The anti-proliferative activity of the compounds was assessed against three different cancer cell lines, namely A549 lung cancer, MCF-7 breast adenocarcinoma, and HepG-2 hepatic carcinoma. Further, promising candidates were evaluated against A549, and MCF-7 and for their ability to inhibit topoisomerases I &II. Compound 5f was observed to be the most active congener, displaying the highest cell inhibition of 84.4% for topoisomerase I and 92%, for topoisomerase II at a concentration of 100 µM. When its cytotoxicity was evaluated against A549 cells, 5f arrested the cell cycle at the S phase and increased the apoptosis ratio by 46.31%. DFT calculation of 5f showed higher dipole moment and greater negative energy values (-247531.510 kcal/mol) with positive & negative poles, and better stability reflection. Furthermore, molecular docking of 5f to both enzymes showed good agreement with the biological assessment. This study has given insight for further consideration of the highly promising hybrid 5f.

Drug repositioning: doxazosin attenuates the virulence factors and biofilm formation in Gram-negative bacteria.

The resistance development is an increasing global health risk that needs innovative solutions. Repurposing drugs to serve as anti-virulence agents is suggested as an advantageous strategy to diminish bacterial resistance development. Bacterial virulence is controlled by quorum sensing (QS) system that orchestrates the expression of biofilm formation, motility, and virulence factors production as enzymes and virulent pigments. Interfering with QS could lead to bacterial virulence mitigation without affecting bacterial growth that does not result in bacterial resistance development. This study investigated the probable anti-virulence and anti-QS activities of α-adrenoreceptor blocker doxazosin against Proteus mirabilis and Pseudomonas aeruginosa. Besides in silico study, in vitro and in vivo investigations were conducted to assess the doxazosin anti-virulence actions. Doxazosin significantly diminished the biofilm formation and release of QS-controlled Chromobacterium violaceum pigment and virulence factors in P. aeruginosa and P. mirabilis, and downregulated the QS encoding genes in P. aeruginosa. Virtually, doxazosin interfered with QS proteins, and in vivo protected mice against P. mirabilis and P. aeruginosa. The role of the membranal sensors as QseC and PmrA was recognized in enhancing the Gram-negative virulence. Doxazosin downregulated the membranal sensors PmR and QseC encoding genes and could in silico interfere with them. In conclusion, this study preliminary documents the probable anti-QS and anti-virulence activities of doxazosin, which indicate its possible application as an alternative or in addition to antibiotics. However, extended toxicological and pharmacological investigations are essential to approve the feasible clinical application of doxazosin as novel efficient anti-virulence agent. KEY POINTS: • Anti-hypertensive doxazosin acquires anti-quorum sensing activities • Doxazosin diminishes the virulence of Proteus mirabilis and Pseudomonas aeruginosa • Doxazosin could dimmish the bacterial espionage.

Design, synthesis and antitumor evaluation of novel pyrazolo[3,4-d]pyrimidines incorporating different amino acid conjugates as potential DHFR inhibitors.

The present study aimed to investigate the antitumor effect of simultaneous inhibition of dihydrofolate reductase (DHFR) enzyme. We designed some novel pyrazolo[3,4-d]pyrimidines bearing different amino acid conjugates as efficient antifolate agents attributable to their structural similarity with methotrexate (MTX) and MTX-related antifolates. All compounds were tested to screen their enzymatic inhibition against DHFR compared with the reference drug MTX and for their in vitro antitumor cytotoxicity against six MTX-resistant cancer cell lines. The flow cytometry indicated that the most potent compound 7f arrested MCF-7 cells in the S-phase and induced apoptosis. Western blot for visualisation proved the ability of compound 7f to induce the expression of proapoptotic caspases and Bax proteins in MCF-7 breast cancer cell line beside its ability to diminish the expression of antiapoptotic Bcl-2 protein. Molecular modelling studies concluded that compound 7f displayed better binding energy than that of the normal ligand MTX. HIGHLIGHTSNew pyrazolo[3,4-d]pyrimidine derivatives 7a-m which are structurally similar to the classical methotrexate (MTX) and MTX-related antifolates were synthesised as antitumor agents.Novel N-acyl amino acid compound 7f exhibited marked DHFR inhibition activity that are parralel to both the molecular docking results and cytotoxic activity.Compound 7f could induce the expression of proapoptotic caspases and Bax proteins in MCF-7 breast cancer cell line beside its ability to diminish the expression of antiapoptotic Bcl-2 protein.All prepared compounds obey Lipinski rule of five except compound 7f.

Human dihydrofolate reductase inhibition effect of 1-Phenylpyrazolo[3,4-d]pyrimidines: Synthesis, antitumor evaluation and molecular modeling study.

A new series of pyrazolo[3,4-d]pyrimidine analogues bearing different amino acid conjugates 10a-m were synthesized with the aim to evaluate their antitumor effect through simultaneous inhibition of human dihydrofolate reductase (hDHFR). All novel compounds were tested to screen their enzyme inhibition activity against (hDHFR) beside their in vitro cytotoxicity against six human MTX resistant cancer cell lines namely, human prostate cancer (PC-3), pancreatic human cancer cell lines (BxPC-3), colorectal carcinoma (HCT-116), human hepatocellular carcinoma (HepG-2), cervical carcinoma (HeLa), and mammary gland breast cancer (MCF-7), besides normal immortalized pancreatic cell line (HPDE). Compounds 10e, 10f, 10g inhibited DHFR at considerable low (IC50 < 1 µM) in comparison to MTX (IC50 = 5.61 µM) beside their characteristic cytotoxic effects on different resistant cancer cell lines. Flow cytometry was done for the most active candidate compound 10e against MCF-7 breast cancer cell line. The results illustrated that compound 10e induced apoptosis and arrested MCF-7 cell cycle in the G1/S phase. Western blot for visualization and quantification was used to confirm the capability of compound 10e to induce the expression of proapoptotic caspases and Bax proteins in MCF-7 breast cancer cell line beside its ability to reduce the expression of antiapoptotic Bcl-2 protein. Molecular modeling studies demonstrated that compound 10e elucidated binding energy of (S= - 8.4390 Kcal/mol) that exceed that of the normal ligand MTX (S= - 8.3951Kcal/mol) in addition to several favorable binding interactions with the active site residues.

Design and synthesis of ibuprofen-quinoline conjugates as potential anti-inflammatory and analgesic drug candidates.

A new set of ibuprofen-quinoline conjugates comprising quinolinyl heterocycle and ibuprofen moieties linked by an alkyl chain were synthesized in good yields utilizing an optimized reaction procedure in a molecular hybridization approach to overcome the drawbacks of the current non-steroidal anti-inflammatory drugs. The synthesized conjugates were screened for their anti-inflammatory, and ulcerogenic properties. Several conjugates were found to have significant anti-inflammatory properties in the carrageenan-induced rat paw edema test without showing any ulcerogenic liability. In addition, most conjugates showed promising peripheral analgesic activity in the acetic acid-induced writhing test as well as central analgesic properties in the in vivo hot plate test. The most promising conjugates were the unsubstituted and 6-substituted fluoro- and chloro-derivatives of 2-(trifluoromethyl)quinoline linked to ibuprofen by a propyl chain. Their anti-inflammatory activity was evaluated against LPS-stimulated inflammatory reactions in RAW264.7 mouse macrophages. In this regard, it was found that most of the conjugates were able to significantly reduce the release and production of nitric oxide in the LPS-stimulated macrophages. The secretion and expression of the pro-inflammatory cytokines IL-6, TNF-α, and inducible nitric oxide synthase (iNOS) were also significantly suppressed.

Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening.

An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields via protecting group-free stepwise unsymmetric diacylation of piperazine using N-acylbenzotiazole. Compounds 3f, 3d, and 3i exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid 3f was found to exhibit higher in vitro potency than donepezil with IC50 = 18 ± 0.2 nM, 29.9 ± 0.15 nM for 3f and donepezil, respectively. 3f was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds 3f, 3d, and 3i are drug-like and can penetrate blood-brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs.

Synthesis, Antimicrobial, Anti-Virulence and Anticancer Evaluation of New 5(4H)-Oxazolone-Based Sulfonamides.

Since the synthesis of prontosil the first prodrug shares their chemical moiety, sulfonamides exhibit diverse modes of actions to serve as antimicrobials, diuretics, antidiabetics, and other clinical applications. This inspiring chemical nucleus has promoted several research groups to investigate the synthesis of new members exploring new clinical applications. In this study, a novel series of 5(4H)-oxazolone-based-sulfonamides (OBS) 9a-k were synthesized, and their antibacterial and antifungal activities were evaluated against a wide range of Gram-positive and -negative bacteria and fungi. Most of the tested compounds exhibited promising antibacterial activity against both Gram-positive and -negative bacteria particularly OBS 9b and 9f. Meanwhile, compound 9h showed the most potent antifungal activity. Moreover, the OBS 9a, 9b, and 9f that inhibited the bacterial growth at the lowest concentrations were subjected to further evaluation for their anti-virulence activities against Pseudomonas aeruginosa and Staphylococcus aureus. Interestingly, the three tested compounds reduced the biofilm formation and diminished the production of virulence factors in both P. aeruginosa and S. aureus. Bacteria use a signaling system, quorum sensing (QS), to regulate their virulence. In this context, in silico study has been conducted to assess the ability of OBS to compete with the QS receptors. The tested OBS showed marked ability to bind and hinder QS receptors, indicating that anti-virulence activities of OBS could be due to blocking QS, the system that controls the bacterial virulence. Furthermore, anticancer activity has been further performed for such derivatives. The OBS compounds showed variable anti-tumor activities, specifically 9a, 9b, 9f and 9k, against different cancer lines. Conclusively, the OBS compounds can serve as antimicrobials, anti-virulence and anti-tumor agents.

Synthesis of Potential Antiviral Agents for SARS-CoV-2 Using Molecular Hybridization Approach.

We synthesized a set of small molecules using a molecular hybridization approach with good yields. The antiviral properties of the synthesized conjugates against the SAR-CoV-2 virus were investigated and their cytotoxicity was also determined. Among all the synthesized conjugates, compound 9f showed potential against SARS-CoV-2 and low cytotoxicity. The conjugates' selectivity indexes (SIs) were determined to correlate the antiviral properties and cytotoxicity. The observed biological data were further validated using computational studies.

Novel 1,2,4-oxadiazole-chalcone/oxime hybrids as potential antibacterial DNA gyrase inhibitors: Design, synthesis, ADMET prediction and molecular docking study.

New antibacterial drugs are urgently needed to tackle the rapid rise in multi-drug resistant bacteria. DNA gyrase is a validated target for the development of new antibacterial drugs. Thus, in the present investigation, a novel series of 1,2,4-oxadiazole-chalcone/oxime (6a-f) and (7a-f) were synthesized and characterized by IR, NMR (1H and 13C) and elemental analyses. The title compounds were evaluated for their in-vitro antimicrobial activity by the modified agar diffusion method as well as their E. coli DNA gyrase inhibitory activity. The minimum inhibitory concentration (MIC) and the structure activity relationships (SARs) were evaluated. Among all, compounds 6a, 6c-e, 7b and 7e were the most potent and proved to possess broad spectrum activity against the tested Gram-positive and Gram-negative organisms. Additionally, compounds 6a (against S. aureus), 6c (against B. subtilis and E. hirae), 6e (against E. hirae), 6f, 7a and 7c (against E. coli) and 7d (against B. subtilis), with MIC value of 3.12 µM were two-fold more potent than the standard ciprofloxacin (MIC = 6.25 µM). Mechanistically, compounds 6c, 7c, 7e and 7b had good inhibitory activity against E. coli gyrase with IC50 values of 17.05, 13.4, 16.9, and 19.6 µM, respectively, in comparison with novobiocin (IC50 = 12.3 µM) and ciprofloxacin (IC50 = 10.5 µM). The molecular docking results at DNA gyrase active site revealed that the most potent compounds 6c and 7c have binding mode and docking scores comparable to that of ciprofloxacin and novobiocin suggesting their antibacterial activity via inhibition of DNA gyrase. Finally, the predicted parameters of Lipinski's rule of five and ADMET analysis showed that 6c and 7c had good drug-likeness and acceptable physicochemical properties. Therefore, the hybridization of the chalcone and oxadiazole moieties could be promising lead as antibacterial candidate which merit further future structural optimizations.

Design, synthesis and pharmacological screening of novel renoprotective methionine-based peptidomimetics: Amelioration of cisplatin-induced nephrotoxicity.

Cisplatin (CP) is an effective chemotherapeutic agent for treatment of various types of cancer, however efforts are needed to reduce its toxic side effect. Previous studies revealed promising effect of peptides in decreasing CP induced nephrotoxicity. Herein, novel Met-based peptidomimetics were synthesized using N-acylbenzotriazole as acylating agent in high yield. Evaluation of renoprotective effect of the synthesized targets on CP treated kidney cell line (LLC-PK1) revealed that pretreatment with 1/3 IC50 of targets II, IIIa-g attenuated CP induced cell death where the IC50 of CP was raised from 3.28 µM to 9.25-41.1 µM. The most potent compounds IIIg, II and IIIb exhibited antioxidative stress in CP-treated LLC-PK1 cells as confirmed by raising GSH/GSSG ratio and SOD concentration as well as decreasing ROS and MDA. Additionally, in vivo experiments using Sprague Dawley rats showed renoprotective effect of IIIg against CP-induced nephrotoxicity as evidenced by improved results of renal function tests and attenuated CP-induced renal structural injury. Moreover, antioxidant activity of IIIg was demonstrated via its ability to reduce renal MDA level and up-regulate renal antioxidant element GSH level. Further, immunohistochemistry of renal specimens showed the ability of IIIg to restore CP-induced suppression of Nrf2. Interestingly, in vivo and in vitro studies demonstrated that IIIg had no effect on CP antiproliferative activity. An assessment of the ADMET properties revealed that targets IIIg, II and IIIb showed good drug-likeness in terms of their physicochemical, pharmacokinetic properties. The findings presented here showcase that IIIg is a promising renoprotective candidate with antioxidative stress potential.

New quinoline-triazole conjugates: Synthesis, and antiviral properties against SARS-CoV-2.

At present therapeutic options for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are very limited. We designed and synthesized three sets of small molecules using quinoline scaffolds. A series of quinoline conjugates (10a-l, 11a-c, and 12a-e) by incorporating 1,2,3-triazole were synthesized via a modified microwave-assisted click chemistry technique. Among the synthesized conjugates, 4-((1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-fluoro-2-(trifluoromethyl)quinoline (10g) and 6-fluoro-4-(2-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)quinoline (12c) show high potency against SARS-CoV-2. The selectivity index (SI) of compounds 10g and 12c also indicates the significant efficacy compared to the reference drugs.

Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction.

Two series of chalcone/aryl carboximidamide hybrids 4a-f and 6a-f were synthesised and evaluated for their inhibitory activity against iNOS and PGE2. The most potent derivatives were further checked for their in vivo anti-inflammatory activity utilising carrageenan-induced rat paw oedema model. Compounds 4c, 4d, 6c and 6d were proved to be the most effective inhibitors of PGE2, LPS-induced NO production, iNOS activity. Moreover, 4c, 4d, 6c and 6d showed significant oedema inhibition ranging from 62.21% to 78.51%, compared to indomethacin (56.27 ± 2.14%) and celecoxib (12.32%). Additionally, 4c, 6a and 6e displayed good COX2 inhibitory activity while 4c, 6a and 6c exhibited the highest 5LOX inhibitory activity. Compounds 4c, 4d, 6c and 6d fit nicely into the pocket of iNOS protein (PDB ID: 1r35) via the important amino acid residues. Prediction of physicochemical parameters exhibited that 4c, 4d, 6c and 6d had acceptable physicochemical parameters and drug-likeness. The results indicated that chalcone/aryl carboximidamides 4c, 4d, 6c and 6d, in particular 4d and 6d, could be used as promising lead candidates as potent anti-inflammatory agents.

Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect.

A new series of quinoline derivatives of combretastatin A-4 have been designed, synthesised and demonstrated as tubulin polymerisation inhibitors. These novel compounds showed significant antiproliferative activities, among them, 12c exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC50 ranging from 0.010 to 0.042 µM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that 12c can inhibit tubulin polymerisation and cell migration, leading to G2/M phase arrest. Besides, 12c induces apoptosis via a mitochondrial-dependant apoptosis pathway and caused reactive oxygen stress generation in MCF-7 cells. These results provide guidance for further rational development of potent tubulin polymerisation inhibitors for the treatment of cancer.HighlightsA novel series of quinoline derivatives of combretastatin A-4 have been designed and synthesised.Compound 12c showed significant antiproliferative activities against different cancer cell lines.Compound 12c effectively inhibited tubulin polymerisation and competed with [3H] colchicine in binding to tubulin.Compound 12c arrested the cell cycle at G2/M phase, effectively inducing apoptosis and inhibition of cell migration.

Design, synthesis, and pharmacological evaluation of novel and selective COX-2 inhibitors based on bumetanide scaffold.

Herein, we describe the design and synthesis of new benzenesulfonamide derivatives as selective COX-2 inhibitors based on bumetanide scaffold. Benzenesulfonamides bearing both the pyrazole 6b and the triazoles 9a, 9c were good inhibitors of COX-2 with IC50 values of 0.32, 0.28 and 0.17 µM, respectively. These benzenesulfonamides 6b, 9a and 9c exhibited a higher selectivity index than the reference drug celecoxib. Molecular modeling study showed that incorporation of bumetanide led to a unique binding mode that is most likely the reason for the observed significant COX-2 selectivity. The anti-inflammatory activity of synthesized compounds revealed that triazoles 9a and 9c demonstrated higher efficacy than celecoxib upon using in vivo carrageenan-induced rat paw edema model. Most of the prepared compounds possess low ulcerogenic potential when administered orally. Therefore, these compounds have a great potential to be developed as safe therapeutics for inflammation, pain, and other diseases where COX-2 plays important role in their pathophysiology.

Design and synthesis of novel pyrazolo[3,4-d]pyrimidin-4-one bearing quinoline scaffold as potent dual PDE5 inhibitors and apoptotic inducers for cancer therapy.

PDE5 targeting represents a new and promising strategy for apoptosis induction and inhibition of tumor cell growth due to its over-expression in diverse types of human carcinomas. Accordingly, we report the synthesis of series of pyrazolo[3,4-d]pyrimidin-4-one carrying quinoline moiety (11a-r) with potential dual PDE5 inhibition and apoptotic induction for cancer treatment. These hybrids were structurally elucidated and characterized with variant spectroscopic techniques as 1H NMR, 13C NMR and elemental analysis. The assessment of their anticancer activities has been declared. All the rationalized compounds 11a-r have been selected for their cytotoxic activity screening by NCI against 60 cell lines. Compounds 11a, 11b, 11j and 11k were the most active hybrids. Among all, compound 11j was further selected for five dose tesing and it displayed outstanding activity with strong antitumor activity against the nine tumor subpanels tested with selectivity ratios ranging from 0.019 to 8.3 at the GI50 level. Further, the most active targets 11a, b, j and k were screened for their PDE5 inhibitory activity, compound 11j (with IC50 1.57 nM) exhibited the most potent PDE5 inhibitory activity. Moreover, compound 11j is also showed moderate EGFR inhibition with IC50 of 5.827 ± 0.46 µM, but significantly inhibited the Wnt/ß-catenin pathway with IC501286.96 ± 12.37 ng/mL. In addition, compound 11j induced the intrinsic apoptotic mitochondrial pathway in HepG2 cells as evidenced by the lower expression levels of the anti-apoptotic Bcl-2 protein, and the higher expression of the pro-apoptotic protein Bax, p53, cytochrome c and the up-regulated active caspase-9 and caspase-3 levels. All results confirmed by western blotting assay. Compound 11j exhibit pre G1 apoptosis and cell cycle arrest at G2/M phase. In conclusion, hybridization of quinoline moiety with the privileged pyrazolo[3,4-d]pyrimidinon-4-one structure resulted in highly potent anticancer agent, 11j, which deserves more study, in particular, in vivo and clinical investiagtions, and it is expected that these results would be applied for more drug discovery process.

Design, synthesis and anticancer activity of novel valproic acid conjugates with improved histone deacetylase (HDAC) inhibitory activity.

Twenty-five valproic acid conjugates have been designed and synthesized. All target compounds were explored for their in vitro anti-proliferative activities using the MTT-based assay against four human cancer cell lines includingliver (HePG2), colon (HCT116), breast (MCF7) and cervical (HeLa) carcinoma cell lines. Out of six valproic acid-amino acid conjugates 2a-f. Only cysteine containing conjugate 2f showed the significant activity (IC50 9.10 µM against HePG2 and 6.81 µM against HCT116). However conjugate 2j showed broad-spectrum antitumor activity against all cell lines tested. In addition, conjugates 4j and 4k which contains phenyl hydrazide and hydroxamic acid group, respectively, also showed broad spectrum activity. Furthermore, six compounds were screened for HDAC 1-9 isozymes inhibitory activities. Compounds 2j, 4j and 4k manifested a higher inhibitory activity more than valproic acid but less than SAHA. In addition, the in vivo antitumor screening of 2j, 4j and 4k was done and the results have shown that 2j, 4j and 4k, particularly 4j, showed a significant decrease in tumor size and presented a considerable decrease in viable EAC count. Docking study of selectedcompound 4j revealed that it can bind nicely to the binding pocket of HDAC 1, 2, 3, 4 and HDAC 8. The results suggest that compounds 2j, 4j and 4k, particularly 4j, may be promising lead candidates for the development of novel targeted anti-tumor drug potentially via inhibiting HDACs.

Design, synthesis and biological evaluation of novel 5-((substituted quinolin-3-yl/1-naphthyl) methylene)-3-substituted imidazolidin-2,4-dione as HIV-1 fusion inhibitors.

A series of novel 5-(substituted quinolin-3-yl or 1-naphthyl)methylene)-3-substituted imidazolidin-2,4-dione 9-26 was designed and synthesized. The prepared compounds were identified using 1H NMR, 13C NMR as well as elemental analyses. The inhibitory activity of 9-26 on HIV-1IIIB replication in MT-2 cells was evaluated. Some derivatives showed good to excellent anti-HIV activities as compounds 13, 18, 19, 20, 22 and 23. They showed EC50 of 0.148, 0.460, 0.332, 0.50, 0.271 and 0.420 µM respectively being more potent than compound I (EC50 = 0.70 µM) and II ( EC50 = 2.40 µM) as standards. The inhibitory activity of 9-26 on infected primary HIV-1 domain, 92US657 (clade B, R5) was investigated. All the tested compounds consistently inhibited infection of this virus with EC50 from 0.520 to 11.857 µM. Results from SAR studies showed that substitution on ring A with 6/7/8-methyl group resulted in significant increase in the inhibitory activity against HIV-1IIIB infection (5- >300 times) compared to the unsubstituted analog 9. The cytotoxicity of these compounds on MT-2 cells was tested and their CC50 values ranged from 11 to 85 µM with selectivity indexes ranged from 0.53 to 166. The docking study revealed nice fitting of the new compounds into the hydrophobic pocket of HIV-1 gp41 and higher affinity than NB-64. Compound 13, the most active in preventing HIV-1IIIB infection, adopted a similar orientation to compound IV. Molecular docking analysis of the new compounds revealed hydrogen bonding interactions between the imidazolidine-2,4-dione ring and LYS574 which were missed in the weakly active derivatives.

Antioxidant Property of the Egyptian Propolis Extract Versus Aluminum Silicate Intoxication on a Rat's Lung: Histopathological Studies.

In this study, we evaluated the inflammatory responses induced by aluminum silicate (AS) cytotoxicity in rat lungs. The prophylactic effect of propolis extract was evaluated in 60 adult male albino rats. The rats were divided into six groups: (1) a normal, healthy control group; (2) a normal group fed with 200 mL of propolis extract/Kg; (3) a low-dose positive control group injected with 5 mg/kg of AS; (4) a treated group given propolis and a low dose of AS; (5) a high-dose positive control group injected with 20 mg/kg of AS; and (6) a treated group given propolis with a high-dose of AS. At the end of the two-month experiment, the rats' lungs were removed. For each pair of lungs, one portion was subjected to biochemical analysis and the other underwent hematoxylin and eosin (H&E) staining in order to study its histology. The rats that received AS doses displayed significant disorders in their antioxidant contents as well as in their enzymatic activities and their histopathological structures revealed severe damage to their lung tissues. Upon the rats being treated with propolis, the enzymatic and antioxidant contents improved and partial improvements in the lung structures appeared, including minimized congestion, a reduced hemorrhage of blood vessels and preserved bronchioles, alveolar ducts, and alveoli. The prophylactic effectiveness of propolis extract on the cytotoxicity of AS, owing to the antioxidant properties of propolis, were studied.