Design, synthesis, computational study and cytotoxic evaluation of some new quinazoline derivatives containing pyrimidine moiety.

Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC50 values ranging from 2.3 ± 5.91 to 176.5 ± 0.7 µM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 ± 1.69 µM, 2.3 ± 5.91 µM and 5.65 ± 2.33 µM against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted.

Barium silicate nanoparticles, an efficient catalyst for one-pot green synthesis of α-benzyl amino coumarin derivatives as potential chemotherapeutic agents.

A new, simple, and efficient method for synthesis of α-benzyl amino coumarin and its derivatives (1-24) is described via a one-pot, three-component condensation of aromatic aldehydes, amine, and 4-hydroxycoumarin under green chemistry conditions: water as a solvent and BaSiO3 nanoparticles as catalyst. BaSiO3 nanoparticles and all synthesized derivatives were characterized by multiple methods including; XRD, NMR, and FE-SEM. This method which gives higher yields, is also less expensive, and more environmentally friendly compared with other methods in the literature. In silico physicochemical and pharmacokinetics analyses were done on all synthesized compounds and indicated that these α-benzyl amino coumarins would be effective scaffolds for the future development of chemotherapeutic agents.

6-Bromoquinazoline Derivatives as Potent Anticancer Agents: Synthesis, Cytotoxic Evaluation, and Computational Studies.

A series of 6-bromoquinazoline derivatives (5a-j) were synthesized. Cytotoxic effectiveness of compounds was done against two cancerous cell lines (MCF-7 and SW480) by standard MTT method. Fortunately, all of the compounds showed desirable activity in reducing the viability of the studied cancerous cell lines with IC50 value in the range of 0.53-46.6 µM. Compound 5b with a fluoro substitution at meta position of the phenyl moiety showed stronger activity than cisplatin with IC50 =0.53-1.95 µM. Studies on the hit compound (5b) through apoptosis assay illustrated that it could induce apoptosis in MCF-7 cell lines in dose dependent manner. Molecular docking study was done to investigate the detailed binding modes and interactions with EGFR as a plausible mechanism. The drug- likeness was predicted. To survey the reactivity of compounds, DFT calculation was performed. Taken together, 6-bromoquinazoline derivatives, especially 5b can be considered as hit compounds to rational drug designing as antiproliferative 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.

Synthesis, biological evaluation, and computational studies of some novel quinazoline derivatives as anticancer agents.

A series of quinazolinone derivatives (7a-7h) were synthesized as antiproliferative agents. All compounds, were synthesized through three steps method and structurally evaluated by FTIR, 1H-NMR, 13CNMR and Mass spectroscopy. Their cytotoxic activities were assessed using MTT protocol against three humans cancerous (MCF-7, A549 and 5637) and normal (MRC-5) cell lines. In addition, molecular docking and simulation studies of the synthesized compounds were performed to assessment their orientation, interaction mode against EGFR as plausible mechanism of quinazoline compounds as anticancer agents. The synthesized compounds mostly showed moderate activity against the three studied cell lines. They also indicated an appropriate selectivity against tumorigenic and non-tumorigenic cell line. The molecular docking results also confirmed biological activity. Most of the compounds fulfilled Lipinski rule. Collectively, these compounds with further modification can be considered as potent antiproliferative agents.

A detailed theoretical exploration on the THR-ß binding affinities and antioxidant activity of some halogenated bisphenols.

Natural halogenated phenolic compounds are unique bioactive structures which share features and physicochemical properties with thyroid hormones, who are essential regulators of neurological development and metabolism processes. Also, these structures can be used as natural antioxidants to minimize the diseases related to oxidative stress. In this work, the binding affinity of 32 natural and synthetic halogenated bisphenols were investigated on thyroid hormone receptor-ß (THR-ß) using the molecular docking, MM/GBSA, molecular dynamics, and a rigorous three-layer ONIOM ((M06-2X/6-31G*:PM6:AMBER) calculation. The desirable potency is observed for binding of selected compounds to THR-ß. The Met313, Asn331, and His435 are the main interacting residues in the binding cavity which involved in the hydrogen and halogen bond interactions with the ligands. The most potent candidate on binding to the active site of THR-ß is presented with respect to the results of mentioned calculations. Moreover, the antioxidant activity of compounds has been investigated using the quantum mechanical calculations. The electrostatic potential surfaces illustrate well the antioxidant capacity of compounds. The halogen substituents increase the antioxidant activity of the most stable conformers. The position and number of OH groups are crucial factors which affect the activity, whereas two adjacent hydroxyl groups enhance the antioxidant activity of selected compounds.Communicated by Ramaswamy H. Sarma.

Quinazoline analogues as cytotoxic agents; QSAR, docking, and in silico studies.

BACKGROUND AND PURPOSE: Synthesis and investigation of pharmacological activity of novel compounds are time and money-consuming. However, computational techniques, docking, and in silico studies have facilitated drug discovery research to design pharmacologically effective compounds. EXPERIMENTAL APPROACH: In this study, a series of quinazoline derivatives were applied to quantitative structure-activity relationship (QSAR) analysis. A collection of chemometric methods were conducted to provide relations between structural features and cytotoxic activity of a variety of quinazoline derivatives against breast cancer cell line. An in silico-screening was accomplished and new impressive lead compounds were designed to target the epidermal growth factor receptor (EGFR)-active site based on a new structural pattern. Molecular docking was performed to delve into the interactions, free binding energy, and molecular binding mode of the compounds against the EGFR target. FINDINGS/RESULTS: A comparison between different methods significantly indicated that genetic algorithm-partial least-squares were selected as the best model for quinazoline derivatives. In the current study, constitutional, functional, chemical, resource description framework, 2D autocorrelation, and charge descriptors were considered as significant parameters for the prediction of anticancer activity of quinazoline derivatives. In silico screening was employed to discover new compounds with good potential as anticancer agents and suggested to be synthesized. Also, the binding energy of docking simulation showed desired correlation with QSAR and experimental data. CONCLUSION AND IMPLICATIONS: The results showed good accordance between binding energy and QSAR results. Compounds Q1-Q30 are desired to be synthesized and applied to in vitro evaluation.

Docking, Synthesis and Evaluation of the Antifungal Activity of Pyrimido [4,5-b]quinolins.

In order to expand the application of Fe3O4@SiO2-SnCl4 in the synthesis of heterocyclic compounds, in this study, we wish to report the use of one-pot three component synthesis of pyrimido [4,5-b]quinolone derivatives ( D1-D16 ) through reaction of 6-amino-2-(methylthio)pyrimidin-4 (3H)-one, dimedone, or 1,3-cyclohexadione and aldehydes in the presence of Fe3O4@SiO2-SnCl4 as an efficient eco-friendly catalyst under ultrasound irradiation. The final aim of this study is evaluation of antifungal activity of resulted products. Synthesis of pyrimido [4,5-b]quinolin derivatives were done via three components coupling reaction of aldehyde, dimedone or 1,3-cyclohexadione and 6-amino-2-(methylthio)pyrimidin-4 (3H)-one in the presence of Fe3O4@SiO2-SnCl4 under ultrasonic irradiation in water at 60 °C. The products structure were studied by FT-IRI, 1H NMR,II and 13C NMRII. All the compounds were screened for antimicrobial activity by broth microdilution methods as recommended by CLSIIII. Considering our results showed that compound ( D13 ) had the most antifungal activity against C. dubliniensis, C. Albicans, C. Tropicalis, and C. Neoformance at concentrations ranging (MIC90) from 1-4 µg/mL. Compounds ( D9 ), ( D10 ), ( D14 ), and ( D15 ) had significant inhibitory activities against C. dubliniensis at concentrations ranging (MIC90) from 4-8 µg/mL, respectively. 5-(3,4-dihydroxyphenyl)-8,8-dimethyl-2-(methylthio)-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-4,6(3H,7H)-dione ( D13 ) exhibited inhibitory and fungicidal activities against the tested yeasts. The specific binding mode or the binding orientation of more efficient compounds to CYP51 active site, have been also performed by molecular modeling investigations and showed that there is a good correlation with biological test.

The synthesis and biological evaluation of nucleobases/tetrazole hybrid compounds: A new class of phosphodiesterase type 3 (PDE3) inhibitors.

Spired by the chemical structure of Cilostazol, a selective phosphodiesterase 3A (PDE3A) inhibitor, several novel hybrid compounds of nucleobases (uracil, 6-azauracil, 2-thiuracil, adenine, guanine, theophylline and theobromine) and tetrazole were designed and successfully synthesized and their inhibitory effects on PDE3A as well as their cytotoxicity on HeLa and MCF-7 cancerous cell lines were studied. Obtained results show the linear correlation between the inhibitory effect of synthesized compounds and their cytotoxicity. In some cases, the PDE3A inhibitory effects of synthesized compounds are higher than the Cilostazol. Besides, compared to a standard anticancer drug methotrexate, some of the synthesized compounds showed the higher cytotoxicity against the HeLa and MCF-7 cancerous cell lines.

Synthesis, Molecular Docking and Cytotoxic Activity Evaluation of Organometallic Thiolated Gold(I) Complexes.

The complex [(PhCH2NC)AuCl], 1, was prepared by the reaction of [(Me2S)AuCl], A, with an equimolar amount of benzyl isocyanide (PhCH2NC) ligand. Through a salt metathesis reaction, the chloride ligand in 1 was replaced by potassium benzothiazole-2-thiolate (Kbt) and potassium benzoimidazole-2-thiolate (Kbi) to afford complexes (PhCH2NC)Au(κ1-S-bt)], 2a and (PhCH2NC)Au(κ1-S-bi)], 2b, respectively, which were characterized by NMR spectroscopy. The cytotoxic activities of 2a and 2b were evaluated against three human cancer cell lines, including A549 (lung), SKOV3 (ovary), and MCF-7 (breast). Our results indicated that 2a exhibited comparable cytotoxicity on investigated cell lines with cisplatin. It showed a good anti-proliferative activity with IC50 of 19.46, 11.76 and 13.27 µM against A549, SKOV3 and MCF-7 cell lines, respectively. The effects of these complexes on the proliferation of the non-tumorigenic epithelial breast cell line (MCF-10A) showed their good selectivity between the tumorigenic and non-tumorigenic cell lines. Molecular docking simulation studies were also conducted to determine the specific binding site and binding mode of the synthesized gold complexes to DNA and thioredoxinreductase (TrxR) as their proposed targets.

Synthesis of some novel dibromo-2-arylquinazolinone derivatives as cytotoxic agents.

Recently the quinazoline derivatives have attracted much attention for their anticancer properties. In this study a series of new brominated quinazoline derivatives (1a-1g) were synthesized in two steps. In the first step we used N-bromosuccinimide to brominate the anthranilamid. Then in the second step we closed the quinazoline ring by different aromatic aldehydes. Our aldehydes contain different electron donating or electron withdrawing groups at different positions of the aromatic ring. The chemical structures of products were confirmed by spectroscopic methods such as IR, 1HNMR, 13CNMR, and mass spectroscopy. The cytotoxic activities of the compounds were assessed on three cancerous cell lines including MCF-7, A549, and SKOV3 using colorimetric MTT cytotoxic assay in comparison with cisplatin as a standard drug. Our results collectively indicated that 1f and 1g, exhibited the best anti-proliferative activities on three investigated cancerous cell lines.

Nano-SnCl4.SiO2, an efficient catalyst for synthesis of benzimidazole drivatives as antifungal and cytotoxic agents.

The concept of green chemistry has made significant impact on many frontages including the use of green solvents or sustainable catalyst materials. Benzimidazole ring is an important nitrogen-containing heterocyclic, which exhibits a broad spectrum of bioactivities and are widely utilized by the medicinal chemists for drug discovery. A simple and efficient method was developed for the synthesis of some benzimidazole derivatives via reaction of o-phenylenediamine and substituted aldehydes in the presence of nano-SnCl4/SiO2 as a mild catalyst. Ten 2-substituted benzimidazole compounds ( J1-J10 ) were synthesized. All compounds were evaluated against different species of yeasts and filament fungi using broth micro dilution method as recommended by clinical and laboratory standard institute. Among these compounds, the active ones were chosen for their cytotoxic activities evaluation against MCF-7 and A549 cell lines using MTT method. Compound J2 showed the best antifungal activity against all tested species. Compounds J5-J7 had also desirable antifungal activities. Our cytotoxic results were also similar to the antifungal activities except for J7 which had no cytotoxic activity.

Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies.

Aromatase inhibitors (AIs) as effective candidates have been used in the treatment of hormone-dependent breast cancer. In this study, we have proposed 300 structures as potential AIs and filtered them by Lipinski's rule of five using DrugLito software. Subsequently, they were subjected to docking simulation studies to select the top 20 compounds based on their Gibbs free energy changes and also to perform more studies on the protein-ligand interaction fingerprint by AuposSOM software. In this stage, anastrozole and letrozole were used as positive control to compare their interaction fingerprint patterns with our proposed structures. Finally, based on the binding energy values, one active structure (ligand 15) was selected for molecular dynamic simulation in order to get information for the binding mode of these ligands within the enzyme cavity. The triazole of ligand 15 pointed to HEM group in aromatase active site and coordinated to Fe of HEM through its N4 atom. In addition, two π-cation interactions was also observed, one interaction between triazole and porphyrin of HEM group, and the other was 4-chloro phenyl moiety of this ligand with Arg115 residue.

Synthesis, Biological Evaluation, and Molecular Docking Studies on the DNA Binding Interactions of Platinum(II) Rollover Complexes Containing Phosphorus Donor Ligands.

Cyclometalated rollover complexes of the type [PtMe(κ2 N,C-bipyO-H)(L)] [bipyO-H=cyclometalated 2,2'-bipyridine N-oxide; L=tricyclohexylphosphine (PCy3 , 2 a), 2-(diphenylphosphino)pyridine (PPh2 py, 2 b), P(OPh)3 (2 c)] were synthesized by treating [PtMe(κ2 N,C-bipyO-H)(SMe2 )] (1) with various monodentate phosphine and phosphite ligands. These complexes were characterized by NMR spectroscopy, and the structure of 2 a was confirmed by single-crystal X-ray diffraction. Complex 1 was treated with bis(diphenylphosphino)methane (dppm) at a 1:1 ratio to give the corresponding [PtMe(κ2 N,C-bipyO-H)(κ1 P-dppm)] (3 b) complex, in which the dppm ligand acts as a monodentate pendant ligand. The biological activities of these complexes were evaluated against a panel of four standard cancer cell lines: lung carcinoma (A549), ovarian carcinoma (OV-90 and SKOV3), and breast carcinoma (MCF-7). Complexes 2 c and especially 3 b indicated effective potent cytotoxic activity regarding the cell lines. Electrophoresis mobility shift assays and molecular-modeling investigations were performed to determine the specific binding mode and the binding orientation of these alkylating agents to DNA. Detection of cellular reactive oxygen species was also determined.

A Comparative QSAR Analysis, Molecular Docking and PLIF Studies of Some N-arylphenyl-2, 2-Dichloroacetamide Analogues as Anticancer Agents.

Dichloroacetate (DCA) is a simple and small anticancer drug that arouses the activity of the enzyme pyruvate dehydrogenase (PDH) through inhibition of the enzyme pyruvate dehydrogenase kinases (PDK1-4). DCA can selectively promote mitochondria-regulated apoptosis, depolarizing the hyperpolarized inner mitochondrial membrane potential to normal levels, inhibit tumor growth and reduce proliferation by shifting the glucose metabolism in cancer cells from anaerobic to aerobic glycolysis. In this study, a series of DCA analogues were applied to quantitative structure-activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis-based multiple linear regression (FA-MLR), principal component regression (PCR), and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were applied to make relations between structural characteristics and cytotoxic activities of a variety of DCA analogues. The best multiple linear regression equation was obtained from genetic algorithms partial least squares, which predict 90% of variances. Based on the resulted model, an in silico-screening study was also conducted and new potent lead compounds based on new structural patterns were designed. Molecular docking as well as protein ligand interaction fingerprints (PLIF) studies of these compounds were also investigated and encouraging results were acquired. There was a good correlation between QSAR and docking results.