New sulfonamide-based glycosides incorporated 1,2,3-triazole as cytotoxic agents through VEGFR-2 and carbonic anhydrase inhibitory activity.

New sulfonamide-triazole-glycoside hybrids derivatives were designed, synthesised, and investigated for anticancer efficacy. The target glycosides' cytotoxic activity was studied with a panel of human cancer cell lines. Sulfonamide-based derivatives, 4, 7 and 9 exhibited promising activity against HepG-2 and MCF-7 (IC50 = 8.39-16.90 µM against HepG-2 and 19.57-21.15 µM against MCF-7) comparing with doxorubicin (IC50 = 13.76 ± 0.45, 17.44 ± 0.46 µM against HepG-2 and MCF-7, rescpectively). To detect the probable action mechanism, the inhibitory activity of these targets was studied against VEGFR-2, carbonic anhydrase isoforms hCA IX and hCA XII. Compoumds 7 and 9 gave favorable potency (IC50 = 1.33, 0.38 µM against VEGFR-2, 66, 40 nM against hCA IX and 7.6, 3.2 nM against hCA XII, respectively), comparing with sorafenib and SLC-0111 (IC50 = 0.43 µM, 53 and 4.8 nM, respectively). Moreover, the docking simulation was assessed to supply better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes that was used for further modification in the anticancer field.

Aloe juvenna Brandham & S.Carter as α-Amylase Inhibitor and Hypoglycaemic Agent with Anti-inflammatory Properties for Diabetes Management.

Despite Aloe's traditional use, Aloe juvenna Brandham & S.Carter is poorly characterized. Other Aloes are known for their antidiabetic activity. This study describes the antidiabetic potentials and phytoconstituents of the A. juvenna leaves methanolic extract (AJME). Twenty-six phytoconstituents of AJME were described using HPLC/MS-MS. Lupeol and vitexin were isolated using column chromatography. The antidiabetic activity of AJME was investigated using an in vivo high-fat diet/streptozotocin-induced diabetic rat model and in vitro α-glucosidase and α-amylase inhibitory activity assays. AJME demonstrated its α-amylase inhibitory activity (IC50=313±39.9 ppm) with no effect on α-glucosidase. In vivo, AJME dose-dependently improved hyperglycaemia in a high-fat diet/streptozotocin-induced diabetic rat model. Notably, the higher dose (1600 mg/kg) of AJME significantly downregulated serum interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-1 genes, suggesting its anti-inflammatory effect. These findings indicate AJME's potential as a significant antidiabetic agent through its α-amylase inhibition, hypoglycaemic, and anti-inflammatory properties.

Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties.

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.

Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers.

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 µM. The highest active derivatives (8a, 8 b, 8d, 9a, and 12b) were selected for IC50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFRWT and mutant EGFRT790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFRWT and EGFRT790M with IC50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFRWT and EGFRT790M.

Microwave-Assisted Rapid Synthesis of Luminescent Tryptophan-Stabilized Silver Nanoclusters for Ultra-Sensitive Detection of Fe(III), and Their Application in a Test Strip.

A new preparation method for extreme fluorescent green emission tryptophan-stabilized silver nanoclusters (Tryp-AgNCs) is presented in this scientific research. The produced silver nanoclusters are dependent on tryptophan amino acid which contributes to normal growth in infants and the sublimation and recovery of human protein, muscles, and enzymes. Herein, we have introduced a green method by using microwave-assisted rapid synthesis. The subsequent silver nanoclusters (AgNCs) have excitation/emission peaks at 408/498 nm and display a considerable selectivity to Fe(III) ions. The tryptophan amino acid molecule was used in the synthesis process as a reducing and stabilizing agent. The Tryp-AgNCs' properties were investigated in terms of morphology, dispersity, and modification of the synthesized particles using different advanced instruments. The luminescent nanoclusters traced the Fe(III) ions by the luminescence-quenching mechanism of the Tryp-AgNCs luminescence. Therefore, the extreme selectivity of the prepared nanoclusters was exhibited to the Fe(III) ions, permitting the sensitive tracing of ferric ions in the lab and in the real environmental samples. The limit of detection for Fe(III) ions based on Tryp-AgNCs was calculated to be 16.99 nM. The Tryp-AgNCs can be efficiently applied to a paper test strip method. The synthesized nanoclusters were used efficiently to detect the Fe(III) ions in the environmental samples. Moreover, we examined the reactivity of Tryp-AgNCs on various human tumor cell lines. The results show that the Tryp-AgNCs exhibited their activity versus the cancer cells in a dose-dependent routine for the perceived performance versus the greatest-used cancer cell lines.

An Eco-Friendly Synthetic Approach for Copper Nanoclusters and Their Potential in Lead Ions Sensing and Biological Applications.

A new preparation route for high-luminescent blue-emission pepsin copper nanoclusters (Pep-CuNCs) is introduced in this work. The synthesized nanoclusters are based on a pepsin molecule, which is a stomach enzyme that works to digest proteins that exist in undigested food. Here, we have developed an eco-friendly technique through microwave-assisted fast synthesis. The resulting copper nanoclusters (CuNCs) exhibit significant selectivity towards Pb(II) ions. The pepsin molecule was utilized as a stabilizer and reducing agent in the production procedure of Pep-CuNCs. The characteristics of the resulting Pep-CuNCs were studied in terms of size, surface modification, and composition using various sophisticated techniques. The CuNCs responded to Pb(II) ions through the fluorescence quenching mechanism of the CuNCs' fluorescence. Thus, great selectivity of Pep-CuNCs towards Pb(II) ions was observed, allowing sensitive determination of this metal ion at lab-scale and in the environment. The CuNCs have detection limits for Pb(II) in very tenuous concentration at a nanomalar scale (11.54 nM). The resulting Pep-CuNCs were utilized significantly to detect Pb(II) ions in environmental samples. Additionally, the activity of Pep-CuNCs on different human tumor cell lines was investigated. The data for the observed behavior indicate that the Pep-CuNCs displayed their activity against cancer cells in a dose dependent manner against most utilized cancer cell lines.

Synthesis of aspirin-curcumin mimic conjugates of potential antitumor and anti-SARS-CoV-2 properties.

Series of piperidone-salicylate conjugates were synthesized through the reaction of 3E,5E-bis(arylidene)-4-piperidones with the appropriate acid chloride of acetylsalicylate in the presence of triethylamine. All the synthesized conjugates reveal antiproliferative properties against A431 (squamous skin) cancer cell line with potency higher than that of 5-fluorouracil. Many of the synthesized agents also exhibit promising antiproliferative properties against HCT116 (colon) cancer cell line, of which 5o and 5c are the most effective with 12.9, 9.8 folds potency compared with Sunitinib. Promising activity is also shown against MCF7 (breast) cancer cell line with 1.19, 1.12 folds relative to 5-fluorouracil. PI-flow cytometry of compound 5c supports the arrest of cell cycle at G1-phase. However, compound 5o and Sunitinib arrest the cell cycle at S-phase. The synthesized conjugates can be considered as multi-targeted tyrosine kinase inhibitors due to the promising properties against VEGFR-2 and EGFR in MCF7 and HCT116. CDOCKER studies support the EGFR inhibitory properties. Compounds 5p and 5i possessing thienylidene heterocycle are anti-SARS-CoV-2 with high therapeutic indices. Many of the synthesized agents show enhanced COX-1/2 properties than aspirin with better selectivity index towards COX-2 relative to COX-1. The possible applicability of the potent candidates discovered as antitumor and anti-SARS-CoV-2 is supported by the safe profile against normal (non-cancer, RPE1 and VERO-E6) cells.

Synthesis, pharmacological profile and 2D-QSAR studies of curcumin-amino acid conjugates as potential drug candidates.

A series of curcumin bis-conjugates 3a-q, 5a-k and 6a-k were synthesized in good yields utilizing an optimized reaction condition. We explored the effect of different amino acids and protecting groups on biological activities of curcumin. The conjugates were screened for anti-inflammatory, analgesic and antimicrobial properties. Some of the conjugates showed promising biological observations with a potency comparable with the standard references. The variations in biological properties concerning different amino acids and protecting groups are interesting observations. Effects of the synthesized conjugates on splenocytes and the production of nitric oxide by lipopolysaccharide-stimulated peritoneal macrophages are correlated with the observed anti-inflammatory properties. We have also established the safety profile of the most active conjugates. Robust 2D-QSAR studies supported and validated biological data.

Novel thiazolidines: Synthesis, antiproliferative properties and 2D-QSAR studies.

A series of N-substituted (Z)-2-imino-(5Z)-ylidene thiazolidines/thiazolidin-4-ones were synthesized and their antiproliferative activities against colon (HCT-116) and breast (MCF7) cancer cell lines were evaluated utilizing an MTT growth assay. A 2D-QSAR investigation was conducted to probe and validate the obtained antiproliferative properties for the thiazolidine derivatives. The majority of the thiazolidines exhibit higher potency against a colon cancer cell line relative to the standard reference. The p-halophenylimino p-anisylidene derivatives exhibited the highest anti-proliferative activity against HCT116 relative to control (IC50 = 8.9-10.0 µM compared to 20.4 µM observed for 5-fluorouracil as positive control). An X-ray study confirmed the Z, Z'-configurations for two examples of the synthesized compounds.

Novel Curcumin Inspired Antineoplastic 1-Sulfonyl-4-Piperidones: Design, Synthesis and Molecular Modeling Studies.

BACKGROUND: Curcumin is a well-known example of plant origin exhibiting promising diverse biological properties such as, anti-inflammatory and antitumor as well as poor pharmacokinetic/pharmacodynamic properties. This is why effective agents based on its chemical scaffold were explored. METHODS: A set of 3,5-bis(ylidene)-1-(alkylsulfonyl)piperidin-4-ones were synthesized in excellent yield (80- 96%) through dehydrohalogenation reaction of 3,5-bis(ylidene)-4-piperidinones with the corresponding alkane sulfonyl chloride in the presence of triethylamine. Antiproliferative properties of the synthesized compounds (dienone/curcumin inspired analogues) were studied by the standard MTT technique. RESULTS: Most of the synthesized compounds revealed antiproliferative properties against HCT116 (colon) and A431 (skin/squamous) cancer cell lines with IC50 values at sub-micromolar level. Compound 36 also exhibited potency against MCF7 (breast) and A549 (lung) cancer cell lines (IC50 = 2.23, 4.27µM, respectively) higher than that of the reference standards (IC50 = 3.15, 5.93µM for 5-fluorouracil and doxorubicin against MCF7 and A549 cell lines, respectively). Cytotoxic properties of the synthesized compounds against non-cancer RPE1 cell line supported the safety profile of the effective agents against normal cells. Molecular modeling (3Dpharmacophore and 2D-QSAR) studies validated the observed bio-properties and explained the parameters governing activity. Inhibitory properties of compounds 27 and 29 (representative examples of the promising antiproliferative agents synthesized) supported their mode of action against topoisomerase IIα. CONCLUSION: The synthesized scaffold is a promising antitumor agent (with special selectivity against colon and skin/squamous cancer cell lines) so, it can be considered for further investigation and development of highly effective hits/leads based on the computational models obtained.

Biological Activity, Apoptotic Induction and Cell Cycle Arrest of New Hydrazonoyl Halides Derivatives.

BACKGROUND: The hydrazonoyl halides are presently an important target in the field of medicinal chemistry. The interest in the chemistry of hydrazonoyl halides is a consequence of the fact that they undergo a wide variety of reactions which provide routes to a myriad of both heterocyclic and acyclic compounds. In addition, they have diverse biological activities such as antiviral, anthelmintic, antiarthropodal, fungicidal, herbicidal, insecticidal, pesticidal, acaricidal and miticidal Activity correlated to the presence of hydrazonoyl halides. Moreover, many applications in both industrial and pharmaceutical fields have been found to be associated with these halides. Depending on the above facts and continuation to our work, we herein report on the evaluation of the anticancer activity of these two halides prepared according to the published work and trying to know their molecular mechanism that they proceed to stop proliferation and metastasis of tumor cells by molecular tools such as real time PCR using different apoptotic genes, and cell cycle assay. OBJECTIVE: The goal of this present study is to bring attention to the biological activities of hydrazonoyl halides and the molecular pathway they follow to exert their role in apoptotic death of cancer cell. METHODS: Synthesis of hydrazonoyl halides 2c and 2f. The cytotoxic effect against different human cancer cell lines PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines as MCF-10 and MCF-12 in a monolayer culture model was evaluated. Their mechanism of action inside cancer cell was evaluated using different molecular tools. CONCLUSION: Strong and promising chemotherapeutic hydrazonoyl halides (2a-2f) were evaluated for their different biological activities. As antimicrobial agents, results indicated that three compounds 2a, 2e and 2f exhibited high activity against two tested gram positive bacteria Staphylococcus aureus, Bacillus subtilis, and gram negative ones Escherichia coli, and Pseudomonas aeruginosa, the rest of the compounds were found to be moderately active against the tested microorganisms. Regarding their antifungal effect, compound 2c exhibited potent and promising effect against Candida albicans, while 2b was the most potent toward Aspergillus flavus Link. The compound 2f has repellent effect. With respect to the in vitro antitumor screening, this was done on different human cancer cell lines; namely PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines; as MCF-10 and MCF-12 (normal breast epithelial cell and non-tumorigenic breast epithelial cell line) in a monolayer culture model where screening has been conducted at 100µg/ml (single dose test). Single dose test (100µg/ml) showed that, in case of PC3, all compounds have cytotoxic activity over 90% inhibition, 4 compounds have cytotoxic activity with 100% inhibition with Human colon cancer cell line, 4 compounds showed over 90% inhibition with MCF7 cell line and 4 compounds showed cytotoxic activity over 90% inhibition with HepG-2. Results of IC50 values for most promising compounds showed compounds with values lower than 20µM for all tested human cancer cell line. The promising hydrazonoyl halide 2c and 2f were selected for molecular study to know how they could act inside cancer cell causing death. Two biochemical tests were performed using the two halides 2c and 2f to predict their mechanism of action against breast carcinoma. Real time PCR analysis indicates that the two compounds induced the apoptosis of MCF7 cells through the up regulation of caspase-3, BAX mediated P53 mechanism but unfortunately, they promote the expression of anti-apoptotic protein BCL2. Also, cell cycle assay was performed using two different cell lines MCF7 and HCT116 and data revealed that the two compounds 2c and 2f induced apoptotic cells death of both lines via cell growth arrest at G2/M phase. In addition, it was noted that 2c induced arrest in the two lines more efficiently than 2f at G2/M phase.

Synthesis & molecular modeling studies of bronchodilatory active indole-pyridine conjugates.

AIM: Synthesis of novel bronchodilatory active indole-pyridine conjugates. Results/methodology: Indole-pyridine conjugates (6a-n, 8a-i and 10a-c) were synthesized in a facile pathway through reaction of 2-[(1-alkyl-1H-indol-3-yl)methylene]malononitriles 4a,b with the corresponding ketone-containing compounds (5a-f, 7a-c and 9a,b) in the presence of sodium alkoxide. Single (6l, 8 g) and powder (6k, 8d) x-ray studies supported the structures. RESULTS: Histamine precontracted isolated tracheal rings of guinea pig exhibited the potent bronchodilation properties of 6c (about double-fold potency relative to the standard reference, theophylline). Some of the synthesized conjugates (8d, 6c, 6f and 6e) revealed promising reduction of IL-8 production during lipopolysaccharide-induced airway inflammatory bioassay. Computational studies (3D pharmacophore, 2D-QSAR 'quantitative structure-activity relationship') showed high approximations to the bronchodilation properties and explained the parameters controlling biological observations.

Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold.

An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC50: 0.3, 6.6 and 7 µM) relative to the standard doxorubicin (IC50: 0.6, 6.8 and 12.8 µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR ß, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.

Contribution to in vitro screening of Egyptian plants for schistosomicidal activity.

CONTEXT: This study is a continuation of our previous work in which a bioassay screening of 346 methanol extracts from 281 Egyptian plant species was carried out for in vitro schistosomicidal activity. OBJECTIVE: Another 309 methanol extracts from 278 plant species were subjected to the bioassay screening using the same technique on viable Schistosoma mansoni Sambon (Schistosomatidae) mature worms in specialized culture medium (Roswell Park Memorial Institute medium 1640) in a trial to discover a source for a schistosomiasis drug from Egyptian flora. MATERIAL AND METHODS: The methanol plant extracts were tested in vitro against viable S. mansoni mature worms in culture medium. Viability of worms was examined after exposure to 100 µg/ml of the extract in the medium for 24 h. Negative (dimethyl sulfoxide) and positive (praziquantel) controls were simultaneously used. Extracts showing schistosomicidal activity were further subjected to determination of their (Lethal concentration) LC50 and LC90 values. RESULTS: Confirmed in vitro antischistosomal activity was found in 42 extracts. Of these, 14 plant species possessed considerably high antischistosomal activity (LC50 ≤ 15 µg/ml), viz. Callistemon viminalis (Soland. Ex Gaertn) Cheel, C. rigidus R.Br., C. speciosus (Sims.) DC, C. citrinus Stapf, Eucalyptus citriodora Hook, E. rostrata Dehnh., Eugenia edulis Vell, E. javanica Lam syn. Syzygium samarangense (Blume) Merril, Melaleuca leucadendron (L.) L., M. stypheloides Sm. (all belong to Myrtaceae), Cryptostegia grandiflora R.Br. (Asclepiadaceae), Zilla spinosa (L.) Prantl (Cruciferae), Ficus trijuja L. (Moraceae) and Fagonia mollis Delile (Zygophylacae). DISCUSSION AND CONCLUSION: These species may represent additional natural sources of bioactive material that deserve further investigation for drug discovery against schistosomiasis.

Screening of natural products for therapeutic activity against solid tumors.

Most of the currently used cancer therapeutics are natural products. These agents were generally discovered based on their toxicity to tumour cells using various bioassays. Although the exact mechanisms of action of the most commonly used cancer therapeutics such as anthracyclins, podophyllotoxins and camptothecin are incompletely understood, it is becoming increasingly clear that these agents often show complex modes of action at the cellular level, interacting with numerous targets. Such complex modes of action may be the very reason for clinical efficacy. For discovering new cytotoxic anticancer drugs sophisticated screening methods were used. The principles of such screening projects conducted, using collections of purified natural products or extracts from plants have been described. By performing simple but robust prescreening tests such as the brine shrimp assay, bioactive extracts can be identified. Extracts (65) prepared from a collection of Egyptian plants were identified that showed cytotoxity on HepG2 cells. Interestingly, 22 (33%) of these raw extracts, induced > 2-fold induction of caspase-cleavage activity in a colon carcinoma cell line, consistent with induction of apoptosis. Only a fraction of the diversity of the biosphere has been tested for biological activity and novel cancer therapeutics remains to be discovered.