Design, synthesis and anticancer/antiestrogenic activities of novel indole-benzimidazoles.

Indole-benzimidazoles have recently gained attention due to their antiproliferative and antiestrogenic effects. However, their structural similarities and molecular mechanisms shared with selective estrogen receptor modulators (SERMs) have not yet been investigated. In this study, we synthesized novel ethylsulfonyl indole-benzimidazole derivatives by substituting the first (R1) and fifth (R2) positions of benzimidazole and indole groups, respectively. Subsequently, we performed 1H NMR, 13C NMR, and Mass spectral and in silico docking analyses, and anticancer activity screening studies of these novel indole-benzimidazoles. The antiproliferative effects of indole-benzimidazoles were found to be more similar between the estrogen (E2) responsive cell lines MCF-7 and HEPG2 in comparison to the Estrogen Receptor negative (ER-) cell line MDA-MB-231. R1:p-fluorobenzyl group members were selected as lead compounds for their potent anticancer effects and moderate structural affinity to ER. Microarray expression profiling and gene enrichment analyses (GSEA) of the selected compounds (R1:p-fluorobenzyl: 48, 49, 50, 51; R1:3,4-difluorobenzyl: 53) helped determine the similarly modulated cellular signaling pathways among derivatives. Moreover, we identified known compounds that have significantly similar gene signatures to that of 51 via queries performed in LINCS database; and further transcriptomics comparisons were made using public GEO datasets (GSE35428, GSE7765, GSE62673). Our results strongly demonstrate that these novel indole-benzimidazoles can modulate ER target gene expression as well as dioxin-mediated aryl hydrocarbon receptor and amino acid deprivation-mediated integrated stress response signaling in a dose-dependent manner.

Synthesis, Anticancer Activity, and In Silico Modeling of Alkylsulfonyl Benzimidazole Derivatives: Unveiling Potent Bcl-2 Inhibitors for Breast Cancer.

A series of alkylsulfonyl 1H-benzo[d]imidazole derivatives were synthesized and evaluated for anticancer activity against human breast cancer cells, MCF-7 in vitro. The cytotoxic potential was determined using the xCELLigence real-time cell analysis, and expression levels of genes related to microtubule organization, tumor suppression, apoptosis, cell cycle, and proliferation were examined by quantitative real-time polymerase chain reaction. Molecular docking against Bcl-2 was carried out using AutoDock Vina, while ADME studies were performed to predict the physicochemical and drug-likeness properties of the synthesized compounds. The results revealed that compounds 23 and 27 were the most potent cytotoxic derivatives against MCF-7 cells. Gene expression analysis showed that BCL-2 was the most prominent gene studied. Treatment of MCF-7 cells with compounds 23 and 27 resulted in significant downregulation of the BCL-2 gene, with fold changes of 128 and 256, respectively. Docking analysis predicted a strong interaction between the compounds and the target protein. Interestingly, all of the compounds exhibit a higher binding affinity toward Bcl-2 than the standard drug (compound 27 vina score = -9.6 kcal/mol, vincristine = -6.7 kcal/mol). Molecular dynamics simulations of compounds 23 and 27 showed a permanent stabilization in the binding site of Bcl-2 for 200 ns. Based on Lipinski and Veber's filters, all synthesized compounds displayed drug-like characteristics. These findings suggest that compounds 23 and 27 were the most promising cytotoxic compounds and downregulated the expression of the BCL-2 gene. These derivatives could be further explored as potential candidates for the treatment of breast cancer.

Synthesis and Structure of Novel Phenothiazine Derivatives, and Compound Prioritization via In Silico Target Search and Screening for Cytotoxic and Cholinesterase Modulatory Activities in Liver Cancer Cells and In Vivo in Zebrafish.

Phenothiazines (PTZ) are antipsychotics known to modulate a variety of neurotransmitter activities that include dopaminergic and cholinergic signaling and have been identified as potential anticancer agents in vitro. However, it is important to also test whether a highly cytotoxic, repurposed, or novel PTZ has low toxicity and neuromodulatory activity in vivo using vertebrate model organisms, such as zebrafish. In this study, we synthesized novel phenothiazines and screened them in vitro in liver cancer and in vivo in zebrafish embryos/larvae. The syntheses of several intermediate PTZ 10-yl acyl chlorides were followed by elemental analysis and determination of 1H NMR and 13C NMR mass (ESI+) spectra of a large number of novel PTZ 10-carboxamides. Cytotoxicities of 28 PTZ derivatives (1-28) screened against Hep3B and SkHep1 liver cancer cell lines revealed five intermediate and five novel leads along with trifluoperazine (TFP), prochlorperazine (PCP), and perphenazine, which are relatively more cytotoxic than the basic PTZ core. Overall, the derivatives were more cytotoxic to Hep3B than SkHep1 cells. Moreover, in silico target screening identified cholinesterases as some of the commonest targets of the screened phenothiazines. Interestingly, molecular docking studies with acetylcholinesterase (AChE) and butyrylcholinesterase proteins showed that the most cytotoxic compounds 1, 3, PCP, and TFP behaved similar to Huprin W in their amino acid interactions with the AChE protein. The highly cytotoxic intermediate PTZ derivative 1 exhibited a relatively lower toxicity profile than those of 2 and 3 during the zebrafish development. It also modulated in vivo the cholinesterase activity in a dose-dependent manner while significantly increasing the total cholinesterase activity and/or ACHE mRNA levels, independent of the liver cancer cell type. Our screen also identified novel phenothiazines, i.e., 8 and 10, with significant cytotoxic and cholinesterase modulatory effects in liver cancer cells; yet both compounds had low levels of toxicity in zebrafish. Moreover, they modulated the cholinesterase activity or expression of ACHE in a cancer cell line-specific manner, and compound 10 significantly inhibited the cholinesterase activity in zebrafish. Accordingly, using a successful combination of in silico, in vitro, and in vivo approaches, we identified several lead anticancer and cholinesterase modulatory PTZ derivatives for future research.

Incorporation of Protecting Groups in Organic Chemistry: A Mini-Review.

The approach of utilizing protecting groups (PGs) in organic chemistry has led to the successful syntheses of an array of useful organic compounds. This strategy has also addressed some of the complexities associated with many organic reactions. These PGs find useful applications in simple and complex reactions that involve the synthesis of large organic compounds such as peptides, and oligosaccharides. The fundamental role of PGs is to prevent undesired reactions that could hinder the progress or completion of such reactions. Ideal PGs must be utilized in this regard to achieve the desired objectives. This review describes the diverse protecting groups found in the literatures, the functional moieties for the protection, deprotection strategies, and their relevant applications in organic synthesis.

Benzimidazoles Against Certain Breast Cancer Drug Targets: A Review

BACKGROUND: Benzimidazoles are widely used scaffolds against various types of cancer, including breast cancer. To this end, anticancer agents must be developed using the knowledge of the specific targets of BC. OBJECTIVE: In this study, we aim to review the compounds used against some of the biomolecular targets of breast cancer. To this end, we present information about the various targets, with their latest innovative studies. CONCLUSION: Benzimidazole ring is an important building block that can target diverse cancer scenarios since it can structurally mimic biomolecules in the human body. Additionally, many studies imply the involvement of this moiety on a plethora of pathways and enzymes related to BC. Herein, our target- based collection of benzimidazole derivatives strongly suggests the utilization of benzimidazole derivatives against BC.

Synthesis, antioxidant activity, molecular docking and ADME studies of novel pyrrole-benzimidazole derivatives.

Several 5-(alkylsulfonyl)-1-substituted-2-(1H-pyrrol-2-yl)-1H-benzo[d]imidazole derivatives were synthesized and their antioxidant activities were investigated using lipid peroxidation (LPO) and 7-ethoxyresorufin O-deethylase (EROD) assays. Docking analysis with Human NAD[P]H-Quinone oxidoreductase 1 (NQO1) was also performed to gather thorough information about these compounds that have antioxidant activities. Moreover, their molecular descriptors and ADME properties were calculated using the SwissADME online program. As a result, most of our compounds possessed better affinity and created ample interactions with NQO1. The most potent compound 5j had LP inhibition value of 3.73 nmol/mg/min. Other compounds exhibited moderate activity on LP levels comparing to standard butylated hydroxy toluene (BHT). However, the inhibitory effect on EROD activity was not significant.

Synthesis, Molecular Docking Studies and Antibacterial Activities of Novel Monocationic Indole-benzimidazole Derivatives.

BACKGROUND: Finding efficient therapy against hospital-acquired MRSA infections has become rather important in the last decade. To this end, inhibition of the enzyme pyruvate kinase (PK) is being investigated for antibacterial activity, since this enzyme controls energy generation and metabolic flux distribution. Our main scaffold consists of benzimidazole and indole rings fused together. Both rings are famous for antibacterial properties and promising anti-MRSA compounds including indole ring. METHODS: Several 1-substituted-2-(1H-indol-3-yl)-N-substituted-1H-benzimidazole-5-carboxamidine analogues were developed, synthesized and their antibacterial activities were evaluated against Staphylococcus aureus (ATCC 25923), Methicillin resistant Staphylococcus aureus (MRSA) (ATCC 43300), and Staphylococcus epidermidis (ATCC 12228) by using tube dilution method. Molecular docking analysis with a characteristic protein called MRSA- Pyruvate Kinase has been conducted for the assessment of the activities of our compounds against Methicillinresistant S. aureus (MRSA). RESULTS: Among all the tested compounds, the most potent compound 36 had MIC values as 3.12, 3.12 and 6.25 µg/mL against S. aureus, Methicillin-resistant S. aureus (MRSA), and S. epidermidis, respectively. This compound had much better docking energy value than standard ampicillin and also created the link between two residues in different monomers of PK. DISCUSSION: This approach of using indol-amidine conjugate systems as anti-MRSA agents may include MRSA-PK as potential target. To further increase the affinity, some other H-bonding parts may be added. By doing so, another bridge with Ile361 residues on both sides can be created. Our compounds tend to violate log P limit of Lipinski, therefore some optimizations with formulation can be made. CONCLUSION: This study mainly includes the design, synthesis and optimization of indolebenzimidazole- amidine derivatives. Docking studies confirmed our results, since our most potent hit compound 36 created the necessary interactions between two chains of MRSA-PK. Further optimization can be considered to increase drug ability.