Synthesis, Characterization, In Vitro Anticancer Potentiality, and Antimicrobial Activities of Novel Peptide–Glycyrrhetinic-Acid-Based Derivatives

Glycyrrhetinic acid (GA) is one of many interesting pentacyclic triterpenoids showing significant anticancer activity by triggering apoptosis in tumor cell lines. This study deals with the design and synthesis of new glycyrrhetinic acid (GA)–amino acid peptides and peptide ester derivatives. The structures of the new derivatives were established through various spectral and microanalytical data. The novel compounds were screened for their in vitro cytotoxic activity. The evaluation results showed that the new peptides produced promising cytotoxic activity against the human breast MCF-7 cancer cell line while comparing to doxorubicin. On the other hand, only compounds 3, 5, and 7 produced potent activity against human colon HCT-116 cancer cell line. The human liver cancer (HepG-2) cell line represented a higher sensitivity to peptide 7 (IC50; 3.30 μg/mL), while it appeared insensitive to the rest of the tested peptides. Furthermore, compounds 1, 3, and 5 exhibited a promising safety profile against human normal skin fibroblasts cell line BJ-1. In order to investigate the mode of action, compound 5 was selected as a representative example to study its in vitro effect against the apoptotic parameters and Bax/BCL-2/p53/caspase-7/caspase-3/tubulin, and DNA fragmentation to investigate beta (TUBb). Additionally, all the new analogues were subjected to antimicrobial assay against a panel of Gram-positive and Gram-negative bacteria and the yeast candida Albicans. All the tested GA analogues 1–8 exhibited more antibacterial effect against Micrococcus Luteus than gentamicin, but they exhibited moderate antimicrobial activity against the tested bacterial and yeast strains. Molecular docking studies were also simulated for compound 5 to give better rationalization and put insight to the features of its structure

Design, Synthesis, Anticancer Evaluation, Enzymatic Assays, and a Molecular Modeling Study of Novel Pyrazole−Indole Hybrids

The molecular hybridization concept has recently emerged as a powerful approach in drug discovery. A series of novel indole derivatives linked to the pyrazole moiety were designed and developed via a molecular hybridization protocol as antitumor agents. The target compounds (5a–j and 7a–e) were prepared by the reaction of 5-aminopyrazoles (1a–e) with N-substituted isatin (4a,b) and 1H-indole-3-carbaldehyde (6), respectively. All products were characterized via several analytical and spectroscopic techniques. Compounds (5a–j and 7a–e) were screened for their cytotoxicity activities in vitro against four human cancer types [human colorectal carcinoma (HCT-116), human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), and human lung carcinoma (A549)] using the MTT assay. The obtained results showed that the newly synthesized compounds displayed good-to-excellent antitumor activity. For example, 5-((1H-indol-3-yl)methyleneamino)-N-phenyl-3-(phenylamino)-1H-pyrazole-4-carboxamide (7a) and 5-((1H-indol-3-yl)methyleneamino)-3-(phenylamino)-N-(4-methylphenyl)-1H-pyrazole-4-carboxamide (7b) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC50 values of 6.1 ± 1.9 and 7.9 ± 1.9 μM, respectively, compared to the standard reference drug, doxorubicin (IC50 = 24.7 ± 3.2 μM). The two powerful anticancer compounds (7a and 7b) were further subjected to cell cycle analysis and apoptosis investigation in HepG2 using flow cytometry. We have also studied the enzymatic assay of these two compounds against some enzymes, namely, caspase-3, Bcl-2, Bax, and CDK-2. Interestingly, the molecular docking study revealed that compounds 7a and 7b could well embed in the active pocket of the CDK-2 enzyme via different interactions. Overall, the prepared pyrazole–indole hybrids (7a and 7b) can be proposed as strong anticancer candidate drugs against various cancer cell lines.publishedVersio

Synthesis and <i>in vitro</i> anticancer activity of pyrazolo[1,5-<i>a</i>]pyrimidines and pyrazolo[3,4-<i>d</i>][1,2,3]triazines

<p>A novel series of pyrazolo[1,5-<i>a</i>]pyrimidines <b>14a–j</b> and pyrazolo[1,5-<i>a</i>]quinazolines <b>18a, b</b> were synthesized <i>via</i> condensation of 5-amino-1<i>H</i>-pyrazoles <b>10a, b</b> with 3-(dimethylamino)-1-aryl-prop-2-en-1-ones <b>11a–e</b> and 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione (<b>15</b>), respectively, in glacial acetic acid. Finally, treatment of <b>10a, b</b> with sodium nitrite (NaNO₂) afforded pyrazolo[3,4-<i>d</i>]triazines <b>20a, b</b>. Structures of compounds were confirmed by their spectral data. These compounds were screened for their <i>in vitro</i> cytotoxic activities against human cancer cell lines (HepG-2 and MCF-7) using 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2<i>H</i>-tetrazolium bromide (MTT) assay. The results reveal that, the compounds <b>14b</b> and <b>14h</b> were the most potent in comparison with doxorubicin. The structure–activity relationship was discussed.</p

Design, Synthesis, Anticancer Evaluation, Enzymatic Assays, and a Molecular Modeling Study of Novel Pyrazole−Indole Hybrids

The molecular hybridization concept has recently emerged as a powerful approach in drug discovery. A series of novel indole derivatives linked to the pyrazole moiety were designed and developed via a molecular hybridization protocol as antitumor agents. The target compounds (5a–j and 7a–e) were prepared by the reaction of 5-aminopyrazoles (1a–e) with N-substituted isatin (4a,b) and 1H-indole-3-carbaldehyde (6), respectively. All products were characterized via several analytical and spectroscopic techniques. Compounds (5a–j and 7a–e) were screened for their cytotoxicity activities in vitro against four human cancer types [human colorectal carcinoma (HCT-116), human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), and human lung carcinoma (A549)] using the MTT assay. The obtained results showed that the newly synthesized compounds displayed good-to-excellent antitumor activity. For example, 5-((1H-indol-3-yl)methyleneamino)-N-phenyl-3-(phenylamino)-1H-pyrazole-4-carboxamide (7a) and 5-((1H-indol-3-yl)methyleneamino)-3-(phenylamino)-N-(4-methylphenyl)-1H-pyrazole-4-carboxamide (7b) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC50 values of 6.1 ± 1.9 and 7.9 ± 1.9 μM, respectively, compared to the standard reference drug, doxorubicin (IC50 = 24.7 ± 3.2 μM). The two powerful anticancer compounds (7a and 7b) were further subjected to cell cycle analysis and apoptosis investigation in HepG2 using flow cytometry. We have also studied the enzymatic assay of these two compounds against some enzymes, namely, caspase-3, Bcl-2, Bax, and CDK-2. Interestingly, the molecular docking study revealed that compounds 7a and 7b could well embed in the active pocket of the CDK-2 enzyme via different interactions. Overall, the prepared pyrazole–indole hybrids (7a and 7b) can be proposed as strong anticancer candidate drugs against various cancer cell lines

Anticancer Activities of Newly Synthesized Chiral Macrocyclic Heptapeptide Candidates

As important cancer therapeutic agents, macrocyclic peptides have recently drawn great attention, mainly because they are synthetically accessible and have lower toxicity towards normal cells. In the present work, we synthesized newly macrocyclic pyridoheptapeptide derivatives. The synthesized derivatives were characterized using standard chemical and spectroscopic analytical techniques, and their anticancer activities against human breast and hepatocellular cancer cells were investigated. Results showed that compounds 1a and 1b were the most effective against hepatocellular (HepG2) and breast (MCF-7) cancer cell lines, respectively

Design, Synthesis and Docking Studies of Novel Macrocyclic Pentapeptides as Anticancer Multi-Targeted Kinase Inhibitors

A series of macrocyclic pyrido-pentapeptide candidates 2&ndash;6 were synthesized by using N,N-bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine 1a,b as starting material. Structures of the newly synthesized compounds were established by IR, 1H and 13C-NMR, and MS spectral data and elemental analysis. The in-vitro cytotoxicity activity was investigated for all compounds against MCF-7 and HepG-2 cell lines and the majority of the compounds showed potent anticancer activity against the tested cell lines in comparison with the reference drugs. Out of the macrocyclic pyrido-pentapeptide based compounds, 5c showed encouraging inhibitory activity on MCF-7 and HepG-2 cell lines with IC50 values 9.41 &plusmn; 1.25 and 7.53 &plusmn; 1.33 &mu;M, respectively. Interestingly, 5c also demonstrated multitarget profile and excellent inhibitory activity towards VEGFR-2, CDK-2 and PDGFR&beta; kinases. Furthermore, molecular modeling studies of the compound 5c revealed its possible binding modes into the active sites of those kinases

Green biosynthesized silver nanoparticles using Acalypha wilkesiana extract control root-knot nematode

Nanoparticles nowadays are an effective control agent against most phytopathogens. However, there are many reports on their antimicrobial activity and little as a nematicide. In this study, green biosynthesis of silver nanoparticles (Ag NPs) using Acalypha wilkesiana aqueous leaf extract was achieved. X-ray diffraction patterns confirmed the crystalline structure with face-centred cubic (fcc), where is the size was nearly 20 nm. SEM images of the Ag NPs show the spherical shape and in the range from 10 to 30 nm. Various functional groups, capping, and stability agents were identified using Fourier transmission infrared spectroscopy (FTIR). The nematicidal activity of biosynthesized Ag NPs conc. 25, 50, and 100 µg/mL were evaluated in vitro against root-knot nematode (Meloidogyne incognita), egg hatching (6 days after) and movement after 24 and 48 h. The Ag NPs (100 µg/ml) application after 48 h was the most effective treatment that showed 53.3% of nematode mortality. Overall, the efficiency of bio-Ag NPs reduced the nematode activity, mortality, egg hatching, and movement of larvae. To our knowledge, this is the first report of nematicidal action of biosynthesized Ag NPs using A. wilkesiana aqueous extract, and it could be recommended to manage the plant-parasitic nematode as it is simple, stable, cost-effective and keep the environment safe