6-Bromo quinazoline derivatives as cytotoxic agents: design, synthesis, molecular docking and MD simulation.

Based on unselectively, several side effects and drug resistance of available anticancer agents, the development and research for novel anticancer agents is necessary. In this study, a new series of quinazoline-4(3H)-one derivatives having a thiol group at position 2 of the quinazoline ring (8a-8 h) were designed and synthesized as potential anticancer agents. The Chemical structures of all compounds were characterized by 1H-NMR, 13C-NMR, and Mass spectroscopy. The antiproliferative activity of all derivatives were determined against two cancer cell lines (MCF-7 and SW480) and one normal cell lines (MRC-5) by the MTT method. Cisplatin, Erlotinib and Doxorubicin were used as positive controls. The results of in vitro screening showed that 8a with an aliphatic linker to SH group was the most potent compound with IC50 values of 15.85 ± 3.32 and 17.85 ± 0.92 µM against MCF-7 and SW480 cell lines, respectively. 8a indicated significantly better potency compared to Erlotinib in the MCF-7 cell line. The cytotoxic results obtained from testing compound 8a on the normal cell line, revealing an IC50 value of 84.20 ± 1.72 µM, provide compelling evidence of its selectivity in distinguishing between tumorigenic and non-tumorigenic cell lines. Structure-activity relationship indicated that the variation in the anticancer activities of quinazoline-4(3H)-one derivatives was affected by different substitutions on the SH position. Molecular docking and MD simulation were carried out for consideration of the binding affinity of compounds against EGFR and EGFR-mutated. The binding energy of compounds 8a and 8c were calculated at -6.7 and - 5.3 kcal.mol- 1, respectively. Compounds 8a and 8c were found to establish hydrogen bonds and some other important interactions with key residue. The DFT analysis was also performed at the B3LYP/6-31 + G(d, p) level for compounds 8a, 8c and Erlotinib. Compound 8a was thermodynamically more stable than 8c. Also, the calculated theoretical and experimental data for the IR spectrum were in agreement. The obtained results delineated that the 8a can be considered an appropriate pharmacophore to develop as an anti-proliferative agent.

Synthesis, biological evaluation, molecular docking, and MD simulation of novel 2,4-disubstituted quinazoline derivatives as selective butyrylcholinesterase inhibitors and antioxidant agents.

Alzheimer's disease is the most prevalent neurodegenerative disorder characterized by significant memory loss and cognitive impairments. Studies have shown that the expression level and activity of the butyrylcholinesterase enzyme increases significantly in the late stages of Alzheimer's disease, so butyrylcholinesterase can be considered as a promising therapeutic target for potential Alzheimer's treatments. In the present study, a novel series of 2,4-disubstituted quinazoline derivatives (6a-j) were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes, as well as for their antioxidant activities. The biological evaluation revealed that compounds 6f, 6h, and 6j showed potent inhibitory activities against eqBuChE, with IC50 values of 0.52, 6.74, and 3.65 µM, respectively. These potent compounds showed high selectivity for eqBuChE over eelAChE. The kinetic study demonstrated a mixed-type inhibition pattern for both enzymes, which revealed that the potent compounds might be able to bind to both the catalytic active site and peripheral anionic site of eelAChE and eqBuChE. In addition, molecular docking studies and molecular dynamic simulations indicated that potent compounds have favorable interactions with the active sites of BuChE. The antioxidant screening showed that compounds 6b, 6c, and 6j displayed superior scavenging capabilities compared to the other compounds. The obtained results suggest that compounds 6f, 6h, and 6j are promising lead compounds for the further development of new potent and selective BuChE inhibitors.

New 3-Hydroxypyridine-4-one Analogues: Their Synthesis, Antimicrobial Evaluation, Molecular Docking, and In Silico ADME Prediction.

INTRODUCTION: Drug resistance to existing antimicrobial drugs has become a serious threat to human health, which highlights the need to develop new antimicrobial agents. METHOD: In this study, a new set of 3-hydroxypyridine-4-one derivatives (6a-j) was synthesized, and the antimicrobial effects of these derivatives were evaluated against a variety of microorganisms using the microdilution method. The antimicrobial evaluation indicated that compound 6c, with an electron-donating group -OCH3 at the meta position of the phenyl ring, was the most active compound against S. aureus and E. coli species with an MIC value of 32 µg/mL. Compound 6c was more potent than ampicillin as a reference drug. RESULT: The in vitro antifungal results showed that the studied derivatives had moderate effects (MIC = 128-512 µg/mL) against C. albicans and A. niger species. The molecular modeling studies revealed the possible mechanism and suitable interactions of these derivatives with the target protein. CONCLUSION: The obtained biological results offer valuable insights into the design of more effective antimicrobial agents.

Azole Derivatives: Recent Advances as Potent Antibacterial and Antifungal Agents.

BACKGROUND: Azoles are the famous and widespread scaffold in the pharmaceutical industry due to their wide range of activities, high efficacy, good tolerability, and oral availability. Furthermore, azole derivatives have attracted attention as potent antimicrobial agents. INTRODUCTION: The purpose of this review is to provide an overview of pharmacological aspects of the main scaffolds of azoles, including imidazole, benzimidazole, triazole, and tetrazole, which possess antimicrobial activity, reported from 2016 to 2020, as well as all of our publication in this field. In addition, we discuss the relationship between structure and activity and molecular docking studies of the azole derivatives to provide critical features and valuable information for the synthesis of novel azole compounds with desirable biological activities. The presented structures in this review have been tested against several bacteria and fungi, such as E. coli and C. albicans, which have been common in all of these studies. RESULTS: A comparison of the reported MIC for tested compounds showed fluconazole base structures as the most active antifungal agents, and triazole derivatives bearing nitrophenyl and coumarin moieties to have the most dominant antibacterial activity. CONCLUSION: Triazole and imidazole scaffolds are more important for designing antimicrobial compounds than other azole derivatives, like benzimidazole or tetrazole. All the most active compounds were observed to fulfill the Lipinski rule.

Design, synthesis and evaluation of novel 1,2,4-triazole derivatives as promising anticancer agents.

Herein, we reported the synthesis of nineteen novel 1,2,4-triazole derivatives including 1,3-diphenyl-2-(1H-1,2,4-triazol-1-yl) propan-1-ones (7a-e), 1-(1,3-diphenylpropan-2-yl)-1H-1,2,4-triazole (8a-c) and 1,4-diphenyl-2-(1H-1,2,4-triazol-1-yl) butane-1,4-diones (10a-k). The structures of these derivatives were confirmed by spectroscopic techniques like IR, 1H-NMR, Mass spectroscopy and Elemental analysis. The cytotoxic activities of the synthesized compounds were evaluated against three human cancer cell lines including MCF-7, Hela and A549 using MTT assay. Compounds 7d, 7e, 10a and 10d showed a promising cytotoxic activity lower than 12 µM against Hela cell line. The safety of these compounds was also, evaluated on MRC-5 as a normal cell line and relieved that most of the synthesized compounds have proper selectivity against normal and cytotoxic cancerous cell lines. Finally, molecular docking studies were also, done to understand the mechanism and binding modes of these derivatives in the binding pocket of aromatase enzyme as a possible target.

Potential of cell-penetrating peptides (CPPs) in delivery of antiviral therapeutics and vaccines.

Viral infections are a great threat to human health. Currently, there are no effective vaccines and antiviral drugs against the majority of viral diseases, suggesting the need to develop novel and effective antiviral agents. Since the intracellular delivery of antiviral agents, particularly the impermeable molecules, such as peptides, proteins, and nucleic acids, are essential to exert their therapeutic effects, using a delivery system is highly required. Among various delivery systems, cell-penetrating peptides (CPPs), a group of short peptides with the unique ability of crossing cell membrane, offer great potential for the intracellular delivery of various biologically active cargoes. The results of numerous in vitro and in vivo studies with CPP conjugates demonstrate their promise as therapeutic agents in various medical fields including antiviral therapy. The CPP-mediated delivery of various antiviral agents including peptides, proteins, nucleic acids, and nanocarriers have been associated with therapeutic efficacy both in vitro and in vivo. This review describes various aspects of viruses including their biology, pathogenesis, and therapy and briefly discusses the concept of CPP and its potential in drug delivery. Particularly, it will highlight a variety of CPP applications in the management of viral infections.