Anticancer therapeutic potential of benzofuran scaffolds.

Benzofuran moiety is the main component of many biologically active natural and synthetic heterocycles. These heterocycles have unique therapeutic potentials and are involved in various clinical drugs. The reported results confirmed the extraordinary inhibitory potency of such benzofurans against a panel of human cancer cell lines compared with a wide array of reference anticancer drugs. Several publications about the anticancer potencies of benzofuran-based heterocycles were encountered. The recent developments of anticancer activities of both natural and synthetic benzofuran scaffolds during 2019-2022 are thoroughly covered. Many of the described benzofurans are promising candidates for development as anticancer agents based on their outstanding inhibitory potency against a panel of human cancer cells compared with reference anticancer drugs. These findings encourage medicinal chemists to explore new areas to improve human health and reduce suffering.

Novel bis-amide-based bis-thiazoles as Anti-colorectal Cancer Agents Through Bcl-2 Inhibition: Synthesis, In Vitro, and In Vivo studies.

BACKGROUND: Some heterocycles having bisamide linkage are receiving much interest due to their remarkable biological potencies and they are naturally occurring. Some bisamides and thiazole derivatives were found to inhibit the protein levels of Bcl-2 significantly. This prompted us to synthesize new bis(heterocyclic) derivatives having bisamide function to explore their anti-cancer activities. METHODS: Novel bis-amide-based bis-thiazoles and thiadiazoles were synthesized by reaction of a new bisthiosemicarbazone with a variety of hydrazonoyl chlorides, a-chloroacetylacetone and haloacetic acid derivatives. Most of the synthesized derivatives were tested for colorectal (HCT-116) and breast (MCF-7) cell lines using the MTT assay, with the apoptotic investigation through flow cytometric and RT-PCR analyses. RESULTS: Some derivatives were found to be highly cytotoxic against HCT-116 cells with an IC50 range of (10.44-13.76 µM) compared to 5-fluorouracil (5-FU) (IC50 = 11.78 µM). One product significantly stimulated apoptotic colorectal cancer cell death by 27.24-fold (50.13% compared to control 1.84%) by arresting the cell cycle at the G2/M phase. The obtained results revealed that compound 7f was more cytotoxic against HCT-116 cells than 5-FU. Compound 7f remarkably enhanced apoptotic colorectal cancer cell death and upregulated the propapoptotic genes (P53, BAX and Capases-3,-8,-9) and downregulated the anti-apoptotic gene, B-cell lymphoma 2 (Bcl-2). In vivo study exhibited that 7f-treatment caused tumor inhibition ratio (TIR%) of 50.45% compared to 54.86% in the 5-FU treatment, with a significant reduction in tumor mass and volume. The anti-tumor activity of compound 7f was accompanied by ameliorated hematological and biochemical analyses, histopathological improvement in treated liver tissues, and the immunohistochemical staining revealed Bcl-2 inhibition in agreement with the in vitro results. CONCLUSION: Compound 7f is an interesting candidate for further development as a chemotherapeutic anti-cancer agent.

Benzofuran as a promising scaffold for the synthesis of novel antimicrobial agents.

INTRODUCTION: The benzofuran moiety constitutes a main component of enormous biologically active natural and synthetic heterocycles. Such heterocycles have distinctive therapeutic potential and are employed in various clinical drugs. A number of publications have dealt with the synthesis and extraction of benzofuran-based heterocycles to investigate their antimicrobial potential. AREAS COVERED: This review describes the antimicrobial activity of various natural and synthetic benzofuran scaffolds. The antimicrobial activity of benzofurans is thoroughly investigated against several bacterial (Gram-positive and Gram-negative) and fungal microorganisms compared with several reference antibiotic drugs. The effects of the electronic nature of substituents on the activity of benzofurans through SAR study were reported. This article also highlights the recent natural and synthetic benzofuran-based organic molecules between 2019-2022 that have had success in terms of their antimicrobial activity. EXPERT OPINION: Many of the described benzofurans are promising candidates as antimicrobial agents based on their activity. Most used antibiotics target infections caused by the gram-positive pathogen S. aureus. Interestingly, most of the described benzofurans are promising inhibitors against S. aureus with either equipotent or more potent activity than the reference antibiotic drugs. These findings will encourage medicinal chemists to explore these new avenues for human health promotion to reduce suffering.

Design and synthesis of new bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazines) and bis((quinoxalin-2-yl)phenoxy)alkanes as anti-breast cancer agents through dual PARP-1 and EGFR targets inhibition.

A number of new 1,ω-bis((acetylphenoxy)acetamide)alkanes 5a-f were prepared then their bromination using NBS furnished the novel bis(2-bromoacetyl)phenoxy)acetamides 6a-f. Reaction of 6a-f with 4-amino-5-substituted-4H-1,2,4-triazole-3-thiol 7a-d and with o-phenylenediamine derivatives 9a and b afforded the corresponding bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazine) derivatives 8a-l and bis(quinoxaline) derivatives 10a-e in good yields. The cytotoxicity of the synthesized compounds as well as apoptosis induction through PARP-1 and EGFR as molecular targets was evaluated. Three compounds, 8d, 8i and 8l, exhibited much better cytotoxic activities against MDA-MB-231 than the drug Erlotinib. Interestingly, compound 8i induced apoptosis in MDA-MB-231 cells by 38-fold compared to the control arresting the cell cycle at the G2/M phase, and its treatment upregulated P53, Bax, caspase-3, caspase-8, and caspase-9 gene levels, while it downregulated the Bcl2 level. Compound 8i exhibited promising dual enzyme inhibition of PARP-1 (IC50 = 1.37 nM) compared to Olaparib (IC50 = 1.49 nM), and EGFR (IC50 = 64.65 nM) compared to Erlotinib (IC50 = 80 nM). These results agreed with the molecular docking studies that highlighted the binding disposition of compound 8i inside the PARP-1 and EGFR protein active sites. Hence, compound 8i may serve as a potential anti-breast cancer agent.

Inhibitory activities of bipyrazoles: a patent review.

INTRODUCTION: Bipyrazole is constituted from two pyrazole units either in their fully aromatic or partially hydrogenated forms. Pyrazoles are widely available in pharmaceutical and agrochemical products. Some pyrazoles are essential parts of commercial drugs in the market. This inspired us to collect the pharmacological activities of bipyrazoles that have potential therapeutic behaviors in several biological aspects but none of them were included in commercial drugs. AREAS COVERED: This review covers all biological and pharmacological potentials of bipyrazole derivatives during 2010-2021. The topics of this review comprised anticancer, antioxidant, anti-inflammatory, antimicrobial, antitubercular, antimalarial, insecticidal activities as well as enzymatic inhibitions. EXPERT OPINION: Bipyrazoles demonstrated a wide array of potent activities against various diseases such as anticancer, antitubercular, anti-inflammatory, and antimicrobial activities. Those are of great benefits for medicinal researchers to develop promising building blocks of bipyrazoles for treatment of diseases. The SAR studies showed that metallated bipyrazoles had better biological activities than bipyrazole ligands. For example, gold(III) and iridium(II) complexes of bipyrazoles were proved to be anticancer agents, and copper(I) as well as silver(I) complexes had excellent antibacterial activities. Several bipyrazoles were reported as antimalarial inhibitors better than chloroquine, the possible COVID-19 drug.

Novel Bis-Thiazole Derivatives: Synthesis and Potential Cytotoxic Activity Through Apoptosis With Molecular Docking Approaches.

A series of bis-thiazoles 5a-g were synthesized from bis-thiosemicarbazone 3 with hydrazonoyl chlorides 4a-g. Reaction of 3 with two equivalents of α-halocarbonyl compounds 6-8, 10, and 12a-d afforded the corresponding bis-thiazolidines 9, 11, and 13a-d, respectively. Condensation of bis-thiazolidin-4-one 9 with different aromatic aldehydes furnished bis-thiazolidin-4-ones 14a-d. Compounds 5a-g, 9, and 13a,c,d were screened in vitro for their cytotoxic activities in a panel of cancer cell lines. Compounds 5a-c, 5f-g, and 9 exhibited remarkable cytotoxic activities, especially compound 5c with potent IC50 value 0.6 nM (against cervical cancer, Hela cell line) and compound 5f with high IC50 value 6 nM (against ovarian cancer, KF-28 cell line). Compound 5f-induced appreciated apoptotic cell death was measured as 82.76% associated with cell cycle arrest at the G1 phase. The apoptotic pathways activated in KF-28 cells treated with 5a, 5b, and 5f were further investigated. The upregulation of some pro-apoptotic genes, bax and puma, and the downregulation of some anti-apoptotic genes including the Bcl-2 gene were observed, indicating activation of the mitochondrial-dependent apoptosis. Together with the molecular docking studies of compounds 5a and 5b, our data revealed potential Pim-1 kinase inhibition through their high binding affinities indicated by inhibition of phosphorylated C-myc as a downstream target for Pim-1 kinase. Our study introduces a set of bis-thiazoles with potent anti-cancer activities, in vitro.

Inhibitory activities of indolizine derivatives: a patent review.

INTRODUCTION: Indolizines are structural isomers with indoles. Although several indole-based commercial drugs are available in the market, none of the indolizine-based drugs are available up-to-date. Natural and synthetic indolizines have a wide-range of pharmaceutical importance such as antitumor, antimycobacterial, antagonist, and antiproliferative activities. This prompted us to search and collect all possible data about the pharmacological importance of indolizine to open an avenue to the researchers in exploring more medicinal applications of such biologically important compounds. AREAS COVERED: The current review article covers the advancements in the biological and pharmacological activities of indolizine-based compounds during the last decade. The covered areas of this work involved anticancer, anti-HIV-1, anti-inflammatory, antimicrobial, anti-tubercular, larvicidal, anti-schizophrenia, CRTh2 antagonist's activities in addition to enzymatic inhibitory activity. EXPERT OPINION: The discovery of indolizine drugs will be a major breakthrough as compared with their widely available drug-containing indole isosteres. Major work collected here was focused on anticancer, anti-tubercular, anti-inflammatory, and enzymatic inhibitory activities. The SAR study of the reported biologically active indolizines is summarized throughout the review whenever highlighted to the rationale the behavior of inhibitory action. Several indolizines with certain functions provided great enhancement in the therapeutic activities comparing with reference drugs.

A highly sensitive, selective and renewable carbon paste electrode based on a unique acyclic diamide ionophore for the potentiometric determination of lead ions in polluted water samples.

Due to the toxicity of lead(ii) to all living organisms as it destroys the central nervous system leading to circulatory system and brain disorders, the development of effective and selective lead(ii) ionophores for its detection is very important. In this work, 1,3-bis[2-(N-morpholino)acetamidophenoxy]propane (BMAPP), belonging to acyclic diamides, was applied as a highly selective lead(ii) ionophore in a carbon paste ion selective electrode for the accurate and precise determination of Pb(ii) ions even in the presence of other interfering ions. Factors affecting the electrode's response behavior were studied and optimized. Scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and FT-IR spectroscopy were used for studying the morphology and response mechanism of the prepared sensor. The lipophilicity of the used ionophore, which contributes to the mechanical stability of the sensor, was studied using the contact angle measurement technique. The selectivity coefficients obtained by the separate solution method (SSM) and fixed interference method (FIM) confirmed the selectivity of the proposed sensor for Pb(ii) ions. The proposed sensor exhibited a Nernstian slope of 29.96 ± 0.34 mV per decade over a wide linear range of 5 × 10-8 to 1 × 10-1 mol L-1 and detection limit of 3 × 10-8 mol L-1 for 2 months with a fast response time (<10 s) and working pH range (2.5-5.5). To further ensure the practical applicability of the sensor, it was successfully applied for the lead(ii) ion determination in different water samples and the obtained data showed an agreement with those obtained by atomic absorption spectroscopy. In addition, it was successfully applied for the potentiometric titration of Pb(ii) against K2CrO4 and Na2SO4.

Synthesis of some new 1,3/ or 1,4-bis(glucopyranosyl-1,2,4-triazol-5-ylthio)propanes/ or butanes as potential antimicrobial agents.

Glucosidation of the appropriate 1,3 or 1,4-bis(4-amino or arylideneamino-2,4-dihydro-3-thioxo-3H-1,2,4-triazol-5-ylthio)propanes or butanes with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide followed by chromatographic separation gave the corresponding N-, S-, and N,S-bis(glucosides). Chemical transformation leading to new functionalities has been achieved. Antimicrobial screening of 10 selected compounds resulted in their activity against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, and Escherichia coli.

Palladium-catalyzed reaction of 4-cyclopentene-1,3-diol monoacetate with Grignard reagents producing hitherto unreachable cis-1,2-isomers.

Reaction of 4-cyclopentene-1,3-diol monoacetate with RMgCl (R = alkyl, aryl) in the presence of a palladium catalyst proceeded with retention of configuration to give cis-1,2-regioisomers as the major products.