Recent Applications of Protoberberines as Privileged Starting Materials for the Development of Novel Broad-Spectrum Antiviral Agents: A Concise Review (2017-2023).

Berberine is a well-known phytochemical with significant antiviral activity against a wide range of viruses. Due to having a unique backbone consisting of four interconnected rings, it can be used as a platform for the design and development of novel semisynthetic antiviral agents. The question here is whether novel broad-spectrum antiviral drugs with enhanced activity and toxicity potential can be obtained by attempting to modify the structure of this privileged lead compound. The present study aims to review the results of recent studies in which berberine and its close analogues (protoberberine alkaloids) have been used as starting materials for the production of new semisynthetic antiviral structures. For this purpose, relevant studies published in high-quality journals indexed in databases such as Scopus, Web of Science, PubMed, etc. in the time frame of 2017 to 2023 were collected. Our selection criterion in the current review focuses on the studies in which protoberberines were used as starting materials for the production of semisynthetic agents with antiviral activity during the indicated time period. Correspondingly, studies were identified in which semisynthetic derivatives with significant inhibitory activity against a wide range of viruses including human immunodeficiency virus (HIV), enterovirus 71 (EV71), zika virus (ZIKV), influenza A/B, cytomegalovirus (CMV), respiratory syncytial virus (RSV), and coxsackieviruses were designed and synthesized. Our conclusion is that, despite the introduction of diverse semisynthetic derivatives of berberine with improved activity profiles compared to the parent natural leads, sufficient derivatization has not been done yet and more studies are needed.

Novel 3-aminobenzofuran derivatives as multifunctional agents for the treatment of Alzheimer's disease.

A novel multifunctional series of 3-aminobenzofuran derivatives 5a-p were designed and synthesized as potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The target compounds 5a-p were prepared via a three-step reaction, starting from 2-hydroxy benzonitrile. In vitro anti-cholinesterase activity exhibited that most of the compounds had potent acetyl- and butyrylcholinesterase inhibitory activity. In particular, compound 5f containing 2-fluorobenzyl moiety showed the best inhibitory activity. Furthermore, this compound showed activity on self- and AChE-induced Aß-aggregation and MTT assay against PC12 cells. The kinetic study revealed that compound 5f showed mixed-type inhibition on AChE. Based on these results, compound 5f can be considered as a novel multifunctional structural unit against Alzheimer's disease.

Synthesis of novel 2-acetamide-5-phenylthio-1,3,4-thiadiazole-containing phenyl urea derivatives as potential VEGFR-2 inhibitors.

A novel series of 2-acetamide-5-phenylthio-1,3,4-thiadiazol derivatives containing a phenyl urea warhead were synthesized and evaluated as antiproliferative agents. The cytotoxic activities of the newly synthesized compounds were evaluated toward three human cancer cell lines, including HT-29, A431, and PC3, as well as normal HDF cells, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The biological results revealed the highest degree of cytotoxic effects for the 4-chloro-containing compound 9e against the A431 cell line. Further assessment by Western blot analysis assay confirmed the induction of apoptosis by compound 9e, with upregulation of Bax and downregulation of Bcl-2 proteins in A431 cancer cells. In addition, compound 9e inhibited the phosphorylation of vascular endothelial growth factor and its receptor (VEGFR-2) in A431 cancer cells while the total level of actin protein was unchanged. These results were confirmed by a three-dimensional cell culture method using the hanging drop technique.

Pyrimidine-based EGFR TK inhibitors in targeted cancer therapy.

Despite significant improvements of new treatment options, cancer continues to represent as one of the most common and fatal disease. The EGFR signaling pathway is considered as a significant approach in targeted therapy of cancers. Blocking the EGFR-driven pathway by inhibiting the intracellular tyrosine kinase domain of EGFR have shown considerable improvement in cancer therapy. In an effort to identify EGFR tyrosine kinase inhibitors (TKI), several small molecules especially pyrimidine containing derivatives have been designed by applying molecular simulation and evaluated the emergence of epigenetic mutation and resistance problems restricted the long-term effectiveness of such medication and explained the need for further investigations in this field. In recent years, the studies have been focused on genetic alterations on EGFR tyrosine kinase domain, which led to the design and synthesis of more selective and effective inhibitors. Herein, we give an overview of the importance and status of EGFR inhibitors in cancer therapy. In addition, we provide an update of the recent advances in design, discovery and development of novel pyrimidine containing compounds as promising selective EGFR TK inhibitors.

Synthesis and radioligand-binding assay of 2,5-disubstituted thiadiazoles and evaluation of their anticonvulsant activities.

In this study, a number of 2,5-disubstituted 1,3,4-thiadiazoles were synthesized using an appropriate synthetic route, and their anticonvulsant activity was determined by the maximal electroshock seizure (MES) test and their neurotoxicity was evaluated by the rotarod test. Additionally, their hypnotic activity was tested using the pentobarbital-induced sleep test. Compounds 7 (ED50 = 1.14 and 2.72 µmol/kg in the MES and sleep tests, respectively) and 11 (ED50 = 0.65 and 2.70 µmol/kg in the MES and sleep tests, respectively) were the most potent ones in the sleep test and anticonvulsant test, showing a comparable activity with diazepam as the reference drug. The results of in vivo studies, especially the antagonistic effects of flumazenil, and also the radioligand-binding assay confirmed the involvement of benzodiazepine (BZD) receptors in the anticonvulsant and hypnotic activity of compounds 7 and 11. Finally, the docking study of compound 11 in the BZD-binding site of the GABAA (gamma-aminobutyric acid) receptor confirmed the possible binding of the compound to the BZD receptors. We concluded that the novel 1,3,4-thiadiazole derivatives with appropriate substitution at positions 2 and 5 of the heterocyclic ring had a good affinity to BZD receptors and showed significant efficacy in the pharmacological tests.

A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy.

The identification of molecular agents inhibiting specific functions in cancer cells progression is considered as one of the most successful plans in cancer treatment. The epidermal growth factor receptor (EGFR) over-activation is observed in a vast number of cancers, so, targeting EGFR and its downstream signaling cascades are regarded as a rational and valuable approach in cancer therapy. Several synthetic EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in recent years, mostly exhibited clinical efficacy in relevant models and categorized into first, second, third and fourth-generation. However, studies are still ongoing to find more efficient EGFR inhibitors in light of the resistance to the current inhibitors. In this review, the importance of targeting EGFR signaling pathway in cancer therapy and related epigenetic mutations are highlighted. The recent advances on the discovery and development of different EGFR inhibitors and the use of various therapeutic strategies such as multi-targeting agents and combination therapies have also been reviewed.

Thiazole in the targeted anticancer drug discovery.

Cancer is known as one of the main causes of death in the world; and many compounds have been synthesized to date with potential use in cancer therapy. Thiazole is a versatile heterocycle, found in the structure of many drugs in use as well as anticancer agents. This review provides an overview of recent advances in thiazole-bearing compounds as anticancer agents with particular emphasis on their mechanism of action in cancerous cells. Chemical designs, structure-activity relationships and relevant preclinical properties have been comprehensively described.

Synthesis and biological evaluation of new coumarins bearing 2,4-diaminothiazole-5-carbonyl moiety.

A series of new coumarin-containing compounds 3a-l and 4a-c was designed and synthesized based on the chalcone-type 4-amino-5-cinnamoylthiazole scaffold 2, and screened for their in vitro anticancer and antioxidant activities. Representatively, the 2-thiomorpholinothiazole derivative 3k with IC50 values of 7.5-16.9 µg/ml demonstrated good cytotoxic effects against tested cell lines MCF-7, HepG2 and SW480. Further investigation by flow cytometric analysis confirmed that this compound induces apoptotic cell death in MCF-7 cells and cause G1-phase arrest in the cell cycle. Moreover, most of compounds had intrinsic potential for radical scavenging activity and ferric-reducing power as investigated by DPPH and FRAP assays.

Synthesis and biological evaluation of 4-amino-5-cinnamoylthiazoles as chalcone-like anticancer agents.

A series of 4-amino-5-cinnamoylthiazoles 3a-p were designed and synthesized as chalcone-like anticancer agents. The synthesized derivatives 3a-p were evaluated for their in vitro antiproliferative activities against three different human cancer cell lines including MCF-7, HepG2 and SW480. Most of compounds could significantly prevent proliferation of tested cell lines. In particular, the pyrrolidine derivative 3e namely (E)-1-(4-amino-2-(pyrrolidin-1-yl)thiazol-5-yl)-3-(2,4-dichlorophenyl)prop-2-en-1-one showed promising activity, especially against HepG2 cells (IC50 = 10.6 µg/ml). Flow cytometric analyses revealed that the prototype compound 3e can prevent the proliferation of HepG2 cells by blockade of the cell cycle at the G2 phase and induction of apoptosis.