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Bone morphogenetic proteins (BMPs) are growth factors that have a vital role in the production of bone, cartilage, ligaments, and tendons. Tumors’ upregulation of bone morphogenetic proteins (BMPs) and their receptors are key features of cancer progression. Regulation of the BMP kinase system is a new promising strategy for the development of anti-cancer drugs. In this work, based on a careful literature study, a library of benzothiophene and benzofuran derivatives was subjected to different computational techniques to study the effect of chemical structure changes on the ability of these two scaffolds to target BMP-2 inducible kinase, and to reach promising candidates with proposed activity against BMP-2 inducible kinase. The results of screening against Lipinski’s and Veber’s Rules produced twenty-one outside eighty-four compounds having drug-like molecular nature. Computational ADMET studies favored ten compounds (11, 26, 27, 29, 30, 31, 34, 35, 65, and 72) with good pharmacokinetic profile. Computational toxicity studies excluded compound 34 to elect nine compounds for molecular docking studies which displayed eight compounds (26, 27, 29, 30, 31, 35, 65, and 72) as promising BMP-2 inducible kinase inhibitors. The nine fascinating compounds will be subjected to extensive screening against serine/threonine kinases to explore their potential against these critical proteins. These promising candidates based on benzothiophene and benzofuran scaffolds deserve further clinical investigation as BMP-2 kinase inhibitors for the treatment of cancer.

Apparently, tubulin inhibitors binding to the colchicine-binding site (CBS) currently have outstanding attention for cancer treatment. So, a series of benzo[b]azonin-2-one derivatives having the same pharmacophoric features as colchicine binding site inhibitors (CBSIs) were synthesized targeting the CBS of β-tubulin. The antiproliferative activities of the newly synthesized compounds were assessed against five different cancer cell lines; HepG-2, MCF-7, MDA-MB-231, HCT-116, and Caco-2. Compounds 7a and 7d displayed promising inhibitory activities against all tested cell lines. They were further estimated towards β-tubulin at CBS along with colchicine (Col) as a reference drug. It was shown that the assessed candidates (7a and 7d) and Col exhibited CBSI activities of 5492, 3771, and 486c.p.m./mg protein, respectively, at a concentration of 10 µM. Furthermore, compound 7d was picked out to assess its effects on apoptosis and cell-cycle profile using Annexin V-FITC and PI staining assay. In addition, the apoptotic activity of 7d was investigated using gene expression analysis of apoptosis-related genes of P53, Bax, Caspases 3 and 9, and Bcl-2 in both treated and untreated cells. Moreover, compound 7d was further assessed through in vivo studies using solid Ehrlich carcinoma (SEC)-bearing mice. Furthermore, both molecular docking and molecular dynamics simulations (for 150 ns) were performed to investigate their mechanism of action as potential CBSIs and give more insights into the behavior of the examined candidates within the β-tubulin subunit of the CBS. On the other hand, in silico ADMET studies were carried out to assess the pharmacokinetic features, drug/lead likeness, and toxicity parameters of the newly synthesized derivatives. Finally, to anticipate the possible changes in the antimitotic activities upon future structural modifications of the investigated compounds, a structure-activity relationship study (SAR) was accomplished.

The usage of nanomaterials for rheumatoid arthritis (RA) treatment can improve bioavailability and enable selective targeting. The current study prepares and evaluates the in vivo biological effects of a novel hydroxyapatite/vitamin B12 nanoformula in Complete Freund’s adjuvant-induced arthritis in rats. The synthesized nanoformula was characterized using XRD, FTIR, BET analysis, HERTEM, SEM, particle size, and zeta potential. We synthesized pure HAP NPs with 71.01% loading weight percentages of Vit B12 and 49 mg/g loading capacity. Loading of vitamin B12 on hydroxyapatite was modeled by Monte Carlo simulation. Anti-arthritic, anti-inflammatory, and antioxidant effects of the prepared nanoformula were assessed. Treated arthritic rats showed lower levels of RF and CRP, IL-1β, TNF-α, IL-17, and ADAMTS-5, but higher IL-4 and TIMP-3 levels. In addition, the prepared nanoformula increased GSH content and GST antioxidant activity while decreasing LPO levels. Furthermore, it reduced the expression of TGF-β mRNA. Histopathological examinations revealed an improvement in joint injuries through the reduction of inflammatory cell infiltration, cartilage deterioration, and bone damage caused by Complete Freund’s adjuvant. These findings indicate that the anti-arthritic, antioxidant, and anti-inflammatory properties of the prepared nanoformula could be useful for the development of new anti-arthritic treatments.

A new class of EGFR PROTACs based on pomalidomide was developed, synthesised, and tested for their cytotoxic activity against a panel of human cancer cells. Compounds 15–21 were showed to be more effective against the four tested cell lines than erlotinib. In particular, compound 16 was found to be the most potent counterpart as it was 5.55, 4.34, 5.04, and 7.18 times more active than erlotinib against MCF-7, HepG-2, HCT-116, and A549 cells, respectively. Compound 15 was revealed to be more active than doxorubicin against the four tested cell lines. Furthermore, the most potent cytotoxic compounds were studied further for their kinase inhibitory effects against EGFRWT and EGFRT790M using HTRF test. Compound 16 showed to be the most effective against both kinds of EGFR, with IC50 values of 0.10 and 4.02 µM, respectively. Compound 16 could effectively degrade EGFR protein through ubiquitination (Dmax = 96%) at 72 h in the tested cells.

Herein we reported the design and synthesis of two series comprising twenty-two benzenesulfonamides that integrate the s-triazine moiety. Target compounds successfully suppressed the hCA IX, with IC50 ranging from 28.6 to 871 nM. Compounds 5d, 11b, 5b, and 7b were the most active analogues, which inhibited hCA IX isoform in the low nanomolar range (KI = 28.6, 31.9, 33.4, and 36.6 nM, respectively). Furthermore, they were assessed for their cytotoxic activity against a panel of 60 cancer cell lines following US-NCI protocol. According to five-dose assay, 13c showed significant anticancer activity than 5c with GI50-MID values of 25.08 and 189.01 µM, respectively. Additionally, 13c’s effects on wound healing, cell cycle disruption, and apoptosis induction in NCI-H460 cancer cells were examined. Further, docking studies combined with molecular dynamic simulation showed a stable complex with high binding affinity of 5d to hCA IX, exploiting a favourable H-bond and lipophilic interactions.HIGHLIGHTSCarbonic anhydrase (CA) inhibitors comprising rigid and flexible linkers were developed.Compound 5d is the most potent CA IX inhibitor in the study (IC50: 28.6 nM).Compounds 5c and 13c displayed the greatest antiproliferative activity towards 60 cell lines.Compound 13c exposed constructive outcomes on normal cell lines, metastasis, and wound healing.Molecular docking and molecular dynamics (MDs) simulation was utilised to study binding mode. Carbonic anhydrase (CA) inhibitors comprising rigid and flexible linkers were developed. Compound 5d is the most potent CA IX inhibitor in the study (IC50: 28.6 nM). Compounds 5c and 13c displayed the greatest antiproliferative activity towards 60 cell lines. Compound 13c exposed constructive outcomes on normal cell lines, metastasis, and wound healing. Molecular docking and molecular dynamics (MDs) simulation was utilised to study binding mode.

A new series of 1H-pyrrole (6a–c, 8a–c), pyrrolo[3,2-d]pyrimidines (9a–c) and pyrrolo[3,2-e][1, 4]diazepines (11a–c) were designed and synthesised. These compounds were designed to have the essential pharmacophoric features of EGFR Inhibitors, they have shown anticancer activities against HCT116, MCF-7 and Hep3B cancer cells with IC50 values ranging from 0.009 to 2.195 µM. IC50 value of doxorubicin is 0.008 µM, compounds 9a and 9c showed IC50 values of 0.011 and 0.009 µM respectively against HCT-116 cells. Compound 8b exerted broad-spectrum activity against all tested cell lines with an IC50 value less than 0.05 µM. Compound 8b was evaluated against a panel of kinases. This compound potently inhibited CDK2/Cyclin A1, DYRK3 and GSK3 alpha kinases with 10–23% compared to imatinib (1–10%). It has also arrested the cell cycle of MCF-7 cells at the S phase. Its antiproliferative activity was further augmented by molecular docking into the active sites of EGFR and CDK2 cyclin A1.

Rheumatoid arthritis (RA) is a long-term autoimmune disease. As nanotechnology has advanced, a growing number of nanodrugs have been used in the treatment of RA due to their unique physical and chemical properties. The purpose of this study was to assess the therapeutic potential of a novel zeolite/vitamin B12 nanocomposite (Nano ZT/Vit B12) formulation in complete Freunds adjuvant (CFA)-induced arthritis. The newly synthesized Nano ZT/Vit B12 was fully characterized using various techniques such as XRD, FT-IR, BET analysis, HERTEM, SEM, practical size, zeta potential, XRF, and EDX. The anti-arthritic, anti-inflammatory, and antioxidant activities as well as the immunomodulation effect of Nano ZT/Vit B12 on the CFA rat model of arthritis were examined. Histopathologic ankle joint injuries caused by CFA intrapedal injection included synovium hyperplasia, inflammatory cell infiltration, and extensive cartilage deterioration. The arthritic rats Nano ZT/Vit B12 supplementation significantly improved these effects. Furthermore, in arthritic rats, Nano ZT/Vit B12 significantly reduced serum levels of RF and CRP, as well as the levels of IL-1 beta, TNF-alpha, IL-17, and ADAMTS-5, while increasing IL-4 and TIMP-3 levels. Nano-ZT/Vit B12 significantly declined the LPO level and increased antioxidant activities, such as GSH content and GST activity, in the arthritic rats. In arthritic rats, Nano ZT/Vit B12 also reduced TGF-beta mRNA gene expression and MMP-13 protein levels. Collectively, Nano ZT/Vit B12 seems to have anti-arthritic, anti-inflammatory, and antioxidant properties, making it a promising option for RA in the future. Funding Agencies|King Salman Center for Disability Research [KSRG-2022-047]

Continuous scientific research is necessary to help in the discovery of new promising remedies for the treatment of COVID-19, caused by the SARS-CoV-2 virus. This current research was aimed at identifying potential novel inhibitors of the SARS-CoV-2 main protease, which represents one of the most important targets in the viral life cycle. Protein data bank file ID: 7JQ2 was used containing the co-crystallized inhibitor MPI5 with the Main protease. A virtual screening process for natural evodiamine compounds was performed through absorption, distribution, metabolism, elimination, and toxicity studies, and the promising hits were docked into the binding site of the enzyme. 13-(4-Chlorobenzoyl)-10-hydroxy-14-methyl-8,13,13 b,14-tetrahydroindolo[2′,3′:3,4]pyrido[2,1- b]-quinazolin-5(7 H)-one (29) interacted favorably with the enzyme; it showed high similarity to MPI5. Molecular dynamic simulations for 29 proved the stability of its binding to SARS-CoV-2 protease over 100 ns; subsequent MMGBSA analysis also supported this principle. Furthermore, 29 elucidated higher limiting action on enzymatic behavior throughout the whole process when compared to MPI5. This provides sufficient evidence for the potential of evodiamine compounds in modern antiviral research, especially compound 29, against the modern COVID-19 pandemic.

Keratoconus (KC) is a serious disease that can affect people of any race or nationality, although the exact etiology and pathogenic mechanism are still unknown. In this study, thirty-two FDA-approved ophthalmic drugs were exposed to virtual screening using docking studies against both the MMP-2 and MMP-9 proteins to find the most promising inhibitors as a proposed computational mechanism to treat keratoconus. Matrix metalloproteinases (MMPs) are zinc-dependent proteases, and MMP inhibitors (MMPIs) are usually designed to interact with zinc ion in the catalytic (CAT) domain, thus interfering with enzymatic activity. In our research work, the FDA-approved ophthalmic medications will be investigated as MMPIs, to explore if they can be repurposed for KC treatment. The obtained findings of the docking study suggest that atenolol and ampicillin are able to accommodate into the active sites of MMP-2 and MMP-9. Additionally, both exhibited binding modes similar to inhibitors used as references, with an ability to bind to the zinc of the CAT. Molecular dynamic simulations and the MM-GBSA binding free-energy calculations revealed their stable binding over the course of 50 ns. An additional pharmacophoric study was carried out on MMP-9 (PDB ID: 1GKC) using the co-crystallized ligand as a reference for the future design and screening of the MMP-9 inhibitors. These promising results open the door to further biological research to confirm such theoretical results.

Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 µM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 µM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 μM, and Topo II catalytic inhibitory effect at a concentration of10 μM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.

2,3-Dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride 1 was prepared via reaction of o-phenylene diamine with oxalic acid followed by chlorosulfonation with excess chlorosulfonic acid. A series of new sulfonylquinoxaline derivatives 2–6 were obtained upon reacting compound 1 with different types of amines. 2,3-Dichloro-6-morpholinosulfonylquinoxaline derivative 6 was subjected to further chemical reactions to afford many derivatives of 6-morpholino 2,3-disubstitutedquinoxalines, thus reaction of compound 6 with different secondary amines yielded mono and di secondary aminoquinoxaline derivatives 7–10 depending on the reactivity difference of the two chlorine atoms. Hydrazinolysis of compound 7 furnished hydrazino quinoxaline derivatives 11a-c. Additionally triazolo and pyrazolyl quinoxaline derivatives 12–14 were obtained through the reaction of compound 11a with phenyl isothiocyanate, formylpyrazole and ethyl acetoacetate. All the synthesized compounds were screened for their antibacterial and antifungal activities. Compounds 7a, 9b, 10a, 10c, 10f and 11c showed good to moderate antimicrobial activity against the tested Gram-positive, Gram-negative bacteria and fungi with MIC values ranging from 2.44 to 180.14 μM. Their MBC values were also evaluated using the same tested microorganisms. Moreover, screening against multi-drug resistant strains revealed the promiscuity of these new derivatives, especially compound 7a that showed comparable antibacterial activity (MIC 4.91–9.82 μM) with Norfloxacin (MIC 2.44–9.80 µM). Furthermore, these compounds were evaluated as DNA Gyrase inhibitors and the obtained results were in the range of 15.69–23.72 µM. Immunomodulatory effect was also investigated and compounds 7a, 11c, 10f, 10c, 10a and 9b showed high immunostimulatory action with ratio (142.6 ± 0.4, 135.7 ± 0.5, 117.8 ± 0. 39, 112.5 ± 0. 83, 86.4 ± 0. 47, 72.8 ± 0. 77) respectively. Molecular docking studies of the promising derivatives into DNA Gyrase binding site proved the usefulness of hybridizing quinoxaline scaffold with SO2 and morpholine moieties as a hopeful strategy in designing new DNA Gyrase binding molecules.

Diabetic foot ulceration is a common complication of an uncontrolled diabetic regimen and is considered a serious type of wound. Matrix metalloprteinases (MMPs) are the common key enzymes in wound management, overexpression of MMPs can lead to chronic wounds and ulcers. Calendula officinalis extract has established its efficacy in treating wounds in folk medicine. In this research work, we will focus on the chemical constituents of this promising herb and will investigate its abilities to target matrix metalloprteinase-8 (MMP-8) and matrix metalloprteinase-9 (MMP-9) proteins through the usage of computer-aided drug design tools. In the current study, several promising dual inhibitors are identified, such as quercetin, isoquercetin, isorhamnetin, and isorhamnetin 3-O glycoside, they showed to be good inhibitors for both enzyme subtypes with greater docking score energies than RND-336, which has been reported as a selective MMP-9 inhibitor. Binding scores and amino acid interactions in addition to molecular dynamics (MD) will be discussed in detail through this research work.

Novel pyrrolo [2,3-b] pyrrole derivatives were synthesized and their hypolipidemic activity was assessed in hyperlipidemic rats. The chemical structures of the new derivatives were confirmed through spectral analysis. Compounds 5 and 6 were revealed to be the most effective hypolipidemic agents, with considerable hypocholesterolemic and hypotriglyceridemic effects. They appear to be promising candidates for creating new powerful derivatives with anti-atherosclerotic and hypolipidemic properties. As for antimicrobial activity, some of the tested compounds showed moderate activity against Pseudomonas aeruginosa: compound 2 revealed an MIC value of 50 μg/mL, compared to 25 μg/mL for ciprofloxacin. Compound 3 showed good antimicrobial activity against Staphylococcus aureus, comparable to ciprofloxacin, and roughly half the activity of ampicillin, according to MIC values. Compound 2 has an MIC approximately 25% of that of clotrimazole against Candida albicans. Compound 2 also showed the highest antioxidant activity with 59% inhibition of radical scavenging activity. Additionally, the cytotoxic activity of these new derivatives 1–7 was investigated and most of them showed good anticancer activity against the three tested cell lines.

New series of [1,2,4]triazolo [4,3-a]quinoxaline and bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives have been designed, synthesized and biologically evaluated for their cytotoxic activities against three tumor cell lines (HePG-2, Hep-2 and Caco-2). Compounds 16e, 21, 25a and 25b exhibited the highest activities against the examined cell lines with IC50 values ranging from 0.29 to 0.90 μM comparable to that of doxorubicin (IC50 ranging from 0.51 to 0.73 μM). The most active members were further evaluated for their topoisomerase II (Topo II) inhibitory activities and DNA intercalating affinities as potential mechanisms for their anti-proliferative activities. Interestingly, the results of Topo II inhibition and DNA binding assays were consistent with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited good Topo II inhibitory activities and DNA binding affinities, comparable to that of doxorubicin. Moreover, the most active compound 25a caused cell cycle arrest at G2/M phase and induced apoptosis in Caco-2 cells. In addition, Furthermore, molecular docking studies were performed for the novel compounds against DNA-Topo II complex to investigate their binding patterns. Based on these studies, it was concluded that DNA binding and/or Topo II inhibition may contribute to the observed cytotoxicity of the synthesized compounds.

Before COVID-19, many viruses have infected humans, so what caused COVID-19 to be considered as a pandemic? COVID-19 belongs to the coronavirus family that includes severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS). This family has caused a large number of deaths all over the world. How risky is the novel coronavirus? People and their careers were disrupted, and many businesses all over the world are now closed. From here, it seems to us that this virus is something that can make people feel afraid. In this article, we will try to understand the severity of this virus, and then disclose the available ways to confront it and ways that might improve the ability to face it, either now or in the future. Upon comparing COVID-19 with seasonal flu, we have found that COVID-19 is about 10 times more deadly, although it is not the most infectious virus. In this review, we will discuss how healthy nutrition and lifestyle may help to prevent and treat diseases, and especially COVID-19. We will focus on how to follow healthy nutrition habits and lifestyles to stop the dangers of COVID-19.

In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G-2, Hep-2, and Caco-2). Compounds 18b, 19b, 23, 25b, and 26 showed strong potencies against all tested cell lines with IC50 values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 µM, comparable with those of doxorubicin (IC50 values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 µM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC50 = 0.97 ± 0.1 and 1.10 ± 0.1 µM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 µM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC50 value of 37.06 ± 1.8 µM. Moreover, apoptosis and cell-cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G-2 cells. It has revealed cell-cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl-2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA-Topo II complex to examine the binding patterns of the synthesized compounds.

A new series of 1,3,4-thiadiazolo-adamantane derivatives were synthesized through molecular hybridization approach, then used as starting material to synthesize chloro and cyano acetamide-thiadiazole derivatives 2, 3. The newly designed compounds 1–3 were treated with different reagents to design 5-adamantyl thiadiazole derivatives 4–17 and evaluate their in vitro anti-proliferative activity against three cancer cell lines (MCF-7, HepG-2 and A549). Doxorubicin was used as a positive control. The most promising compounds 5, 6, 10a, 10b, 14b, 14c, and 17 showed up-regulation for BAX and down-regulation of Bcl-2, these findings proved their role as hopeful apoptotic inducers. In addition, the inhibitory activity against both wild EGFRWT and mutant EGFRL858R-TK for these derivatives revealed that compounds 5, 14c, and 17 have IC50 value ranging from 85 nM to 71.5 nM against wild EGFRWT and 37.85–41.19 nM against the mutant type, Lapatinib was used as a reference standard with IC50 values of 31.8 nM and 39.53 nM, respectively. The most potent derivatives were subjected to further evaluation against double mutant EGFR L858R/T790M and showed good IC50 values between (0.27–0.78 nM) compared to Lapatinib (0.18 nM) and Erlotinib (0.21 nM). Among them, thiazolo-thiadiazole adamantane derivative 17 exhibited the strongest inhibitory activity to the EGFR. Molecular docking studies were performed inside the active site of EGFR (1M17), and binding energy scores ranged between (−19.19 to –22.07 Kcal/mol) compared to Erlotinib (−19.10 Kcal/mol). Furthermore, oral bioavailability beside some pharmacokinetics properties of these derivatives were also investigated in this research work.

A series of new VEGFR-2 inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against hepatocellular carcinoma (HepG-2 cell line). Compound 29b (IC50 = 4.33 ± 0.2 µg/ml) was found to be the most potent derivative as it has showed to be more active than doxorubicin (IC50 = 4.50 ± 0.2 µg/ml) and 78% of sorafenib activity (IC50 = 3.40 ± 0.25 µg/ml). The inhibitory profiles against VEGFR-2 were also assessed for the most promising candidates (16b, 20c, 22b, 24a, 24b, 28c, 28e, 29a, 29b and 29c). Compounds 29b, 29c and 29a exhibited potent inhibitory activities towards VEGFR-2 at IC50 values of 3.1 ± 0.04, 3.4 ± 0.05 and 3.7 ± 0.06 µM, respectively, comparing sorafenib (IC50 = 2.4 ± 0.05 µM). Furthermorer, compound 29b induced apoptosis and arrested the cell cycle growth at G2/M phase. Additionally, in vivo antitumor experiments revealed that compounds 29b and 29c have significant tumor growth inhibition. The test of immuno-histochemical expression of activated caspase-3 revealed that there is a time-dependent increase in cleaved caspase-3 protein expression upon exposure of HepG-2 cells to compound 29b. Moreover, the fibroblastic proliferative index test revealed that compound 29b could attenuate liver fibrosis. Docking studies also supported the results concluded from the biological screening via prediction of the possible binding interactions of the target compounds with VEGFR-2 active sites using the crystal structure of VEGFR-2 downloaded from the Protein Data Bank, (PDB ID: 2OH4) using Discovery Studio 2.5 software. Further structural optimization of the most active candidates may serve as a useful strategy for getting new lead compounds in search for powerful and selective antineoplastic agents.

Multi-targeted anticancer drugs are in focus as a promising research topic. A new series of benzothiazoles hybridized with pyrimidine moiety was designed and synthesized using the lead compound 4a. Various chemical modifications on the pyrimidine ring of 4a at four different positions were done in a trial to get new multi-targeted anticancer agents. The structures of the newly synthesized compounds were established on their elemental analyses and spectral data. All final synthesized derivatives were submitted to the National Cancer Institute (NCI), USA, to be screened for their in vitro anticancer activity. Further evaluation for the cytotoxic activity of the most active compounds was performed using the MTT assay method. Compounds 4d, 8d, 8h, 8i and 17 were then selected for examining their in vitro enzyme inhibitory activities against EGFR, HER2 and TS enzymes using lapatinib and 5FU as standards. Furthermore, cell cycle analysis and apoptosis induction detection were also evaluated. Finally, molecular docking studies were carried out for compounds 4d, 8d, 8h, 8i and 17 to interpret their observed enzymatic activities based on the ligand-protein interactions.

New series of 5-(morpholinosulfonyl) isatin derivatives were designed and synthesized. The new compounds were characterized on the basis of spectral and elemental analyses. They were examined for their cytotoxic effects using SRB assay on four cancer cell lines HepG2, HCT116, CACO and MCF-7 in addition to the non-cancerous human cell line. They were non cytotoxic towards the normal derived cell line (IC50 value > 130 μM). Compounds 3, 6, 10 and 11 showed IC50 values less than 10 μM on three of the tested cell lines HepG2, HCT116 and CACO. Compounds 2h, 5, and 7b showed IC50 values less than or nearly equal 10 μM on HepG2, CACO and HCT116 respectively. Compounds 3 and 6 revelaed IC50 values less than 12 μM on MCF7. These obtained IC50 values are comparable with that of doxrubicin as it has showed IC50 range from 4.5 to 8.28 μM on the tested cell lines. All these promising derivatives showed inhibitory activity against EGFR with IC50 values less than 2 μM. The most potent EGFR inhibitors 7b (IC50 = 46 nM) and 10 (IC50 = 23 nM) showed to cause cell cycle arrest at G2/M phase and induce apoptosis. Molecular docking studies also were simulated to put insight and make better understanding to their structural features.

Fifteen new derivatives of quinazolin-4-one bearing the 2-furyl moiety at position 2 and a substituted phenyl moiety at position 3 were designed and synthesized to be evaluated as cytotoxic agents. Their chemical structures were confirmed by spectral and elemental analysis; cytotoxic activity evaluation was performed against HEPG2, HCT116, and MCF7 cancer cell lines using the sulforhodamine-B assay. All the tested compounds except 6a showed high potency against the HEPG2 cancer cell line (IC50 8-101 nM/mL); 11 compounds out of 15 proved to be potent against HCT116 cells (IC50 3-49 nM/mL), also 11 of the tested compounds showed high potency against MCF7 cells with IC50 values ranging from 7 to 63 nM/mL. The rest of the tested compounds showed IC50 values of more than 100 nM/mL. Compounds 3e and 4d are the most active compounds against HEPG2 cells; in addition, 3e is the most active compound against MCF7 cells. Also, compounds 4a, 3a, and 3b are the most active compounds against HCT116 cells. Compounds 3a, 3b, 3e, 4a, and 4d were also evaluated for their inhibitory activity against the EGFR tyrosine kinase (EGFR-TK) and showed a percentage inhibitory activity ranging from 53 to 84%. The most potent EGFR-TK inhibitors, 3a (84%), 3b (75%), and 3e (60%), were docked into the ATP binding site of the EGFR to explore their binding mode and possible interactions.

A new series of pyrrolizine derivatives 4–8c were synthesized, their structures were confirmed by spectral and elemental analyses. Cytotoxic activity of these compounds was evaluated against breast (MCF7), colon (HCT116) and liver (HEPG2) cancer cell lines using sulphorhodamine-B (SRB) assay method. All the tested compounds showed highly potent activity against MCF7 cell line with IC 50 range equal 8–194 nM/ml and compound 8c was the best active one (IC 50 = 8.6 nM/ml). 8b was the best active compound on both HCT116 and HEPG-2 cancer cell lines; its IC 50 is 26.5 and 12.3 nM/ml respectively. Docking studies into ATP binding site of EGFR tyrosine kinase were performed to predict their scores and mode of binding to amino acids, moreover, inhibitory activity of these compounds against EGFR-TKs was evaluated; their inhibitory percent ranged from 40.4 to 97.6, compound 8c and 8b showed inhibitory activity at 97.6% and 88.4% respectively.

A series of novel phthalimide analogs containing an indole or brominated indole moiety were synthesized and their antimicrobial activity was evaluated. Compound 8 showed a broad spectrum activity, revealing 53-67% of erythromycin activity on the tested bacteria and 60-70% of miconazole activity on the tested fungi. Anticancer activity was evaluated on the cell lines HepG2, MCF-7, A549, H1299, and Caco2. The results revealed that the new phthalimide analog 8 has broad-spectrum anticancer activity toward all the tested cancer cell lines, followed by compound 11, which showed good activity toward all the tested cell lines except for MCF-7. The ability of the promising analogs 5, 8, and 11 to bind to topoisomerase II DNA gyrase was investigated. Caspase-3 activation and Bcl-2 assay of the best active derivatives 8, 11 in addition to compound 5 were evaluated. The antifibrotic activity was studied in an in vivo model and the histopathological studies revealed that treatment with the new compound 8 improved the fibrotic liver tissues to normality.

Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quinazoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti-proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26b, 29a, 29b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 µM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC50 value of 2.5 ± 0.04 µM, almost equal to that of sorafenib (IC50 = 2.4 ± 0.05 µM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed significant tumor growth inhibition effect. Molecular docking studies were also performed and finally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities.

A novel series of pyrrolo[1,2-a]azepine derivatives 3-7 were synthesized and their structures were confirmed by spectral and elemental analyses. Antitumor activity evaluation of these compounds was carried out against liver (HepG2), breast (MCF7), and colon (HCT116) cancer cell lines using the sulforhodamine-B (SRB) assay method and doxorubicin as reference standard. Compounds 3 and 6 were found to be more potent than doxorubicin against HepG2 cells, with IC50 values of 4, 1.6 and 10.8 nM, respectively. Moreover, compounds 3 and 7 showed broad-spectrum anticancer activity against all the tested cell lines, and their IC50 values were in the nanomolar range (4-44.2 nM and 20.7-45.4 nM, respectively). The 2-benzoylamino derivative of pyrrolo[1,2-a]azepine 5b was the most potent one against MCF7 cells (IC50 of 10.7 nM); however, the 2-(2-chloro-acetylamino)-pyrroloazepine derivative 6 was the most potent against the HCT116 cell line, with an IC50 value of 21.1 nM. The novel compounds were docked into the active site of cyclin-dependent kinase 2 (CDK2) to explore the ability of these compounds to interact with these kinases. All compounds showed a lower binding score energy than the reference ligand.

Two series of novel 5-arylazo-3-cyano-2-(2&Prime, 3&Prime, 4&Prime, 6&Prime, tetra-O-acetyl-&beta, d-galacto pyranosyloxy) pyridines and 3-cyano-2-(2&Prime, d-galactopyranosyloxy) pyridines were synthesized in high yields utilizing a microwave-assisted synthesis tool guided by the principles of green chemistry. The chemical structures of the new substances were confirmed on the basis of their elemental analysis and spectroscopic data (FT-IR, 1D, 2D-NMR). Activity against different bacterial strains was studied. The anticancer potential of the new compounds is also discussed. Molecular docking was used as a tool in this research work to get better insight into the possible interactions, affinities, and expected modes of binding of the most promising derivatives of the potential chemotherapeutic target (DHFR).

Pyrrolizine derivatives constitute a class of heterocyclic compounds which can serve as promising scaffolds for anticancer drugs. The unique antitumor properties of mitomycin C inspired chemists to develop different pyrrolizine systems and assess their potential antitumor activities against a wide variety of cancer types. Here we review the different classes of pyrrolizines that possess anticancer potency, with an emphasis on their structure activity relationships, in an effort to pave the way for further development in this promising area of research.

A new series of benzothiazoles and benzoxazoles was synthesized using 4-benzothiazol-2-yl-phenylamine and 4-benzoxazol-2-yl-phenylamine as starting materials. All the prepared compounds were evaluated for their antitumor activities against human breast cancer cell lines, MCF-7 and MDA-231, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability analysis. Almost all the tested compounds revealed potent antitumor activity, especially the N-methyl piperazinyl substituted derivatives 6f and 6c, which displayed the most potent inhibitory activity with IC50 values ranging from 8 to 17 nM. Docking the synthesized compounds into the epidermal growth factor receptor (EGFR), which is highly expressed in breast cancer, was employed to explore the possible interactions of these compounds with the EGFR. The activity of the reported compounds supports its clinical promise as a component of therapeutic strategies for cancer, for which high concentrations of chemotherapeutic agents are always a major limitation.

Tamoxifen (TAM) is used for the treatment and prevention of estrogen receptor positive breast cancer. However, the limited activity, toxicity and the development of resistance raised the current need for new potent nontoxic antiestrogen. Six novel TAM analogues 5a–f were synthesized using McMurry olefination reaction. Replacement of the dimethylamino group in TAM by piperidino, piperazino or N-methyl piperazino, substituting the phenyl ring with florine atom at p-position and changing the ethyl group by methyl, afforded compounds showing comparable activity to TAM (1). Compounds 5c and 5e showed significant increase in antiproliferative activity in two breast cancer cell lines (MCF-7 and MDA-MB-231) compared to tamoxifen, while other compounds showed similar activity. The increased anticancer activity of compounds 5c and 5e was attributed to their ability to induce ER-independent cell death.