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.

Triethylsulfonium-based ionic liquids enforce lithium salt electrolytes.

The demand for cheap production of energy and its efficient storage is huge nowadays. Sulfonium-based ionic liquids have exhibited a useful set of physical-chemical and electrochemical properties, which make them good prospective electrolytes for electrochemical double-layer capacitors and rechargeable lithium batteries. The ability of the researchers to correctly describe local ionic structural patterns in the electrochemical systems is a cornerstone of achieving sustainable progress in this field. Herein, we report an in silico investigation of a few lithium-triethylsulfonium electrolytes and correlate our results with the recently published electrochemical study. All chosen organic and inorganic anions have been recently used in the supercapacitor and lithium-battery electrolyte systems: bis(trifluoromethylsulfonyl)imide, perchlorate, hexafluorophosphate, and trifluoromethanesulfonate. Analyzing potential energy surfaces, ion-ionic coordination, electron density distributions, and structure properties, we identified that the best-performing electrolyte system is lithium bis(trifluoromethylsulfonyl)imide dissolved in triethylsulfonium bis(trifluoromethylsulfonyl)imide. In the mentioned system, we found the weakest cation-anion binding that resulted in the fastest ionic transport. The lithium-ion plays a paramount role in the coordination of all investigated anions, whereas the impact of the triethylsulfonium cation is relatively insignificant. The lithium-induced structural changes in the local order of the electrolyte are reflected by computed vibrational spectra. In the lithium-free systems, the anions strongly bind the triethylsulfonium cation via its electron-deficient α-methyl groups. Some of these electrostatically driven interactions may be classified as medium-strength hydrogen bonds. The computed cohesion energies explain the conductivity and viscosity trends obtained for similar electrolyte compositions in the recent experiments. The reported results will be interesting for researchers who develop Li-based energy storage devices that use room-temperature ionic liquids as non-volatile and electrochemically stable media.

Synthesis of some novel 8-(4-Alkylpiperazinyl) caffeine derivatives as potent anti-Leishmania agents.

In this paper, the synthesis, characterization and the leishmanicidal assessments of novel 8-(4-alkylpiperazinyl) caffeine derivatives have been described. These compounds are new caffeine hybrid molecules that are structurally composed of three compartments comprising caffeinyl, piperazinyl and N-alkyl/aryl residues. The synthesis was carried out through the bromination of caffeine via NBS to attain the 8-bromocaffeine (8-BC) followed by the SNAr-type reaction with the piperazine which afforded the 8­piperazinyl caffeine (8-PC). Ultimately, the N-alkylation of 8-PC with diverse alkyl halides acquired the products in good to excellent yields (68-96 %). The in vitro evaluation of synthesized compounds on promastigotes of Leishmania major (MHOM/IR/2002/Mash2) has showed that compounds 9d (ie: 8-(4-heptylpiperazin-1-yl)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione), 9e (ie: 1,3,7-trimethyl-8-(4-octylpipera zin-1-yl)-1H-purine-2,6(3H,7H)-dione) and 9f (ie: 8-(4-decylpiperazin-1-yl)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione) with IC50 = 84 µM, IC50 = 94 µM and IC50 = 89 µM displayed remarkable leishmanicidal activity even stronger than metronidazole (MTZ) and miltefosine as the reference drugs. The SAR analysis indicated the leishmanicidal activity of title compounds depended upon the type of substituents on N4 of piperazine. The in silico physicochemical properties, pharmacokinetic profile, and drug likeness predictions were also carried out for the all synthesized compounds and MTZ. The molecular docking study was also conducted to predict the binding mode and the interaction of 9d as the most and 9a as the least active compounds with pteridine reductase 1 (PTR1) enzyme. The docking results determined that 9d exhibited a strong binding affinity to the active site of the enzyme.

Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their ß-adrenoceptor blocking property.

The design, synthesis, antinociceptive and ß-adrenoceptor blocking activities of several eugenyloxy propanol azole derivatives have been described. In this synthesis, the reaction of eugenol with epichlorohydrin provided adducts 3 and 4 which were N-alkylated by diverse azoles to obtain the eugenyloxy propanol azole analogues in good yields. Adducts 3 and 4 were also reacted with azide ion to obtain the corresponding azide 6. The 'Click' Huisgen cycloaddition reaction of 6 with diverse alkynes afforded the title compounds in good yields. The synthesized eugenyloxy propanol azole derivatives were in vivo studied for the acute antinociception on male Spargue Dawley rats using tail-flick test. Compounds 5f, 5g, 7b and 11a exhibited potent analgesic properties in comparison with eugenol as a standard drug. In addition, all compounds were ex vivo tested for ß-adrenoceptor blocking properties on isolated left atrium of male rats which exhibited partial antagonist or agonist behaviour compared to the standard drugs. The molecular docking study on the binding site of transient receptor potential vanilloid subtype 1 (TRPV1) has indicated that like capsaicin, eugenyloxy propanol azole analogues exhibited the strong affinity to bind at site of TPRV1 in a "tail-up, head-down" conformation and the presence of triazolyl moieties has played undeniable role in durable binding of these ligands to TRPV1. The in silico pharmacokinetic profile, drug likeness and toxicity predictions carried out for all compounds determined that 5g can be considered as potential antinociceptive drug candidate for future research.

Design, synthesis and biological evaluation of novel 1,2,3-triazolyl ß-hydroxy alkyl/carbazole hybrid molecules.

The design, synthesis and biological study of several novel 1,2,3-triazolyl [Formula: see text]-hydroxy alkyl/carbazole hybrid molecules as a new type of antifungal agent has been described. In this synthesis, the N-alkylation reaction of carbazol-9-ide potassium salt with 3-bromoprop-1-yne afforded 9-(prop-2-ynyl)-9H-carbazole. The 'Click' Huisgen cycloaddition reaction of 9-(prop-2-ynyl)-9H-carbazole with diverse [Formula: see text]-azido alcohols in the presence of copper-doped silica cuprous sulphate led to target molecules in excellent yields. The in vitro antifungal and antibacterial activities of title compounds were screened against various pathogenic fungal strains, Gram-positive and/or Gram-negative bacteria. In particular, 1-(4-((9H-carbazol-9-yl) methyl)-1H-1,2,3-triazol-1-yl)-3-butoxypropan-2-ol (10e) proved to have potent antifungal activity against all fungal tests compared with fluconazole and clotrimazole as studied reference drugs. Our molecular docking analysis revealed an appropriate fitting and a potential powerful interaction between compound 10e and an active site of the Mycobacterium P450DM enzyme. The strong hydrogen bondings between [Formula: see text]-hydroxyl and ether groups in 10e were found to be the main factors that drive the molecule to fit in the active site of enzyme. The in silico pharmacokinetic studies were used for a better description of 10a-10n as potential lead antifungal agents for future investigations.

Design, synthesis, and biological activities of novel azole-bonded ß-hydroxypropyl oxime O-ethers.

The synthesis and biological effects of 15 novel azole-bonded ß-hydroxypropyl oxime O-ethers have been described. In this synthesis, the oximation of aromatic ketones followed by an O-alkylation reaction with epichlorohydrin and/or epibromohydrin led to the corresponding O-oxime ether adducts. Subsequently, the attained O-oxime ether adducts were used to synthesize the target molecules after treating them with the appropriate azole derivatives. The in vitro antifungal and antibacterial activities of title compounds were obtained against several pathogenic fungi, Gram-positive and/or Gram-negative bacteria. Benzophenone O-2-hydroxy-3-(2-phenyl-1 H-imidazol-1-yl) propyl oxime and 9H-fluoren-9-one O-2-hydroxy-3-(2-phenyl-1 H-imidazol-1-yl)propyl oxime proved to have considerable antifungal activity against Candida albicans, Candida krusei, Aspergillus niger, and Trichophyton rubrum. These two compounds demonstrated comparable antifungal activity to clotrimazole and fluconazole (standard drugs). All compounds were also tested against Escherichia coli and Staphylococcus aureus as Gram-negative and Gram-positive bacteria, respectively, and their activities were compared to gentamycin and ampicillin (reference drugs). In general, marginal antibacterial activity against tested bacteria was observed for the title compounds. A molecular docking study is also discussed for the two most potent compounds against fungi. The docking study reveals a considerable interaction between the two most potent compounds and the active site of Mycobacterium P450DM. Moreover, these two compounds are much strongly bound to the active site of Mycobacterium P450DM compared to fluconazole.

Design, synthesis, anticancer and in silico assessment of 8-caffeinyl chalcone hybrid conjugates.

In this paper, we report the design, synthesis, and characterization of novel 8-caffeinyl chalcone hybrid conjugates, which were studied for their anticancer properties, toxicity, and in silico behavior. The synthesized compounds consist of 8-caffeinyl and chalcone structures with diverse substituents. The synthesis involved three main stages: bromination of caffeine to produce 8-BC, synthesis of chalcones, and subsequent coupling of these chalcones with 8-BC. The anticancer activity of the resulting compounds was evaluated in vitro against breast cancer MCF-7 and melanoma A-375 cell lines, revealing certain compounds to have significant efficacy compared to the reference drug methotrexate. Toxicity assessments using a healthy cell line indicated that most compounds displayed some level of toxicity, with only a few exceptions. Molecular docking studies indicated robust binding affinities of selected compounds to B-RAF kinase and hDHFR enzymes. In silico analyses of pharmacokinetic and physicochemical properties demonstrated that the majority of the compounds adhered to Lipinski's rule of five. Furthermore, density functional theory (DFT) studies were performed to gain deeper insights into the properties of the intermediates used throughout the research.

Design, synthesis, analgesic, antibacterial and docking studies of novel 8-piperazinylcaffeine carboxylate ionic liquids.

This paper presents a comprehensive evaluation of novel 8-piperazinylcaffeine carboxylate ionic liquids, including their design, synthesis, characterization, analgesic and antibacterial properties, as well as docking studies. These unique salts were produced by combining 8-piperazinyl caffeine (8-PC) with various carboxylic acids, some of which are commonly used nonsteroidal anti-inflammatory drugs (NSAIDs). Through in vivo experiments on female mice using the formalin test, the analgesic efficacy of different 8-PC salts with various NSAIDs was assessed. Results demonstrated that a majority of these salts exhibited significant analgesic activity when compared to NaIBP, a standard reference drug. Particularly noteworthy was the enhanced analgesic effect of the 8-PC's NSAIDs salts (11a, 11c-e, and 11k) compared to their corresponding sodium salts, which was attributed to the presence of the 8-PC cation (synergistic effect). Furthermore, all synthesized salts were subjected to in vitro testing against Gram-positive Staphylococcus aureus (PTCC 1133), Gram-negative Pseudomonas aeruginosa (ATCC 27853), and Escherichia coli (PTCC 1330) bacteria. Among them, salt 11k displayed notable antibacterial activity, especially against P. aeruginosa, a dangerous opportunistic pathogen. Additionally, docking analysis revealed strong binding of the synthesized 8-PC and NSAID salts to the active site of the COX-2 enzyme.

Synthesis, design, biological evaluation, and computational analysis of some novel uracil-azole derivatives as cytotoxic agents.

The design and synthesis of novel cytotoxic agents is still an interesting topic for medicinal chemistry researchers due to the unwanted side effects of anticancer drugs. In this study, a novel series of uracil-azole hybrids were designed and synthesized. The cytotoxic activity, along with computational studies: molecular docking, molecular dynamic simulation, density functional theory, and ADME properties were also, evaluated. The compounds were synthesized by using 3-methyl-6-chlorouracil as the starting material. Cytotoxicity was determined using MTT assay in the breast carcinoma cell line (MCF-7) and Hepatocellular carcinoma cell line (HEPG-2). These derivatives demonstrated powerful inhibitory activity against breast and hepatocellular carcinoma cell lines in comparison to Cisplatin as positive control. Among these compounds, 4j displayed the best selectivity profile and good activity with IC50 values of 16.18 ± 1.02 and 7.56 ± 5.28 µM against MCF-7 and HEPG-2 cell lines respectively. Structure-activity relationships revealed that the variation in the cytotoxic potency of the synthesized compounds was affected by various substitutions of benzyl moiety. The docking output showed that 4j bind well in the active site of EGFR and formed a stable complex with the EGFR protein. DFT was used to investigate the reactivity descriptors of 4a and 4j. The outputs demonstrated that these uracil-azole hybrids can be considered as potential cytotoxic agents.

Design, synthesis, anticancer and in silico assessment of 8-piperazinyl caffeinyl-triazolylmethyl hybrid conjugates.

In this paper, we have assessed the design, synthesis, characterization, anticancer properties, toxicity, and in silico study of 8-piperazinyl caffeinyl-triazolylmethyl derivatives as new caffeine hybrid conjugates. These compounds consist of four moieties comprising 8-caffeinyl, piperazinyl, 1,2,3-triazolyl, and alkyl substituents. The synthesis of these compounds was started by bromination of caffeine to attain 8-BC, SNAr reaction with piperazine to acquire 8-PC, N-propargylation of 8-PC and finally click Huisgen cycloaddition with diverse alkyl azides. These compounds were in vitro tested against two significant cancer cell lines comprising breast cancer MCF-7 (ATCC HTB-22) and melanoma cancer A-375 (ATCC CRL-1619) cell lines and activities compared with methotrexate (MTX) as a reference drug. Anticancer assessments indicated 12j (IC50 = 323 ± 2.6) and 12k (IC50 = 175 ± 3.2) were the most potent compounds against A-375 and MCF-7 cell growth, respectively and their activities were even stronger than MTX (IC50 = 418 ± 2 for A375 and IC50 = 343 ± 3.6 for MCF-7). Toxicities were determined by screening compounds against normal cell line HEK-293 (ATCC CRL-11268) and indicated that except 12i (IC50 = 371 ± 2.3), 12j (IC50 = 418 ± 2.4), and MTX (IC50 = 199 ± 2.4), all compounds are non-toxic. Docking was conducted for 12j and 12k and determined the strong binding affinities to B-RAF kinase and hDHFR enzymes, respectively. In silico pharmacokinetic and physiochemical profiles of tested compounds were investigated which indicated that most compounds obeyed Lipinski's rule of five (RO5). The DFT study on M06-2X/6-311G (d,p) was used to indicate HOMO, LUMO, MEP, and other parameters for a better understanding of 12j and 12k reactivity. Owing to anticancer properties, toxicity, and in silico data, 12j and 12k can be proposed for further research in the future.

Design, synthesis, anticancer and in silico assessment of 8-caffeinyl-triazolylmethoxy hybrid conjugates.

In this research the synthesis, characterization, anticancer and the cytotoxicity assessments of novel 8-caffeinyl-triazolylmethoxy hybrid conjugates have been described. These compounds are the first caffeine-1,2,3-triazolyl hybrid molecules that structurally are composed of three compartments comprising caffeinyl, 1,2,3-triazolyl and N-alkyl/aryl residues. The in vitro evaluations of synthesized compounds on cancer cell lines, including two breast cancer cell lines MDA-MB-468 (ATCC HTB-22), MCF-7 (ATCC HTB-22), melanoma cell line A-375 (ATCC CRL-1619) and normal cell line HEK-293 (ATCC CRL-11268) have determined that 22c (IC50 < 12.5 µM) demonstrated potent activity against A375 and its toxicity is even stronger than methotrexate (MTX) as a standard drug. Additionally, 22c involves more selectivity than MTX regarding its non-toxicity for the HEK-293 cell line. Among the tested compounds against two breast cancer cell lines, 22f (IC50 = 136 ± 0.2 and 126 ± 0.6 µM for MCF-7 and MDA-MB-468, respectively) and 22i (IC50 = 165 ± 1.8 and 175 ± 1.4 µM for MCF-7 and MDA-MB-468, respectively) were the most potent compounds but their activities were less than MTX, moreover 22f showed more selectivity regarding its lower toxicity against HEK-293. Overall, 22f displayed general toxicity and selectivity on all tested cancer cell lines. The in silico physicochemical properties, pharmacokinetic profile, and drug likeness predictions were also carried out for all the studied compounds. Most new compounds exhibited zero violation of Lipinski's rule (RO5). A molecular docking study was also conducted to predict the binding mode and the interaction of 22c as the most active anti-melanoma entry with B-RAF V600E kinase enzyme. The docking results determined that 22c exhibited a strong binding affinity to the active site of the enzyme. These findings demonstrated 22c and 22f as potential future anticancer drug candidates.

Design, synthesis, in silico ADME, DFT, molecular dynamics simulation, anti-tyrosinase, and antioxidant activity of some of the 3-hydroxypyridin-4-one hybrids in combination with acylhydrazone derivatives.

Tyrosinase is the rate-limiting enzyme in synthesizing melanin. Melanin is responsible for changing the color of fruits and vegetables and protecting against skin photo-carcinogenesis. Herein, some of the hybrids of 3-hydroxypyridine-4-one and acylhydrazones were designed and synthesized to study the anti-tyrosinase and antioxidant activities. The diphenolase activity of mushroom tyrosinase using L-DOPA assayed the inhibitory effects, and the antioxidant activity was assessed using DPPH free radical. The synthesized derivatives were confirmed using 1H-NMR, 13C-NMR, IR, and Mass spectroscopy. Among analogs, compound 5h bearing furan ring with IC50=8.94 µM was more potent than kojic acid (IC50=16.68 µM). The pharmacokinetic profile of the compounds showed that the tested compounds had suitable oral bioavailability and drug-likeness properties. The molecular docking studies showed that compound 5h was located in the tyrosinase-binding site. Also, the molecular dynamics simulation was performed on compound 5h, proving the obtained molecular docking results. At the B3LYP/6-31 + G** level of theory, the reactivity descriptors for 5 g and 5h were investigated using DFT calculations. Also, IR frequency was calculated to verify DFT results with experimental data. The electrostatic potential energy of the surface and the HOMO and LUMO molecular orbitals were also studied. It agrees with experimental results that the 5h is a soft molecule and ready for chemical reaction with other interacting molecules.Communicated by Ramaswamy H. Sarma.

Novel 1,4 benzothiazine 3-one derivatives as anticonvulsant agents: Design, synthesis, biological evaluation and computational studies.

In this study, two series of novel 1,4-benzothiazine-3-one derivatives with alkyl substitution (series 1: 4a-4f) and aryl substitution (series 2: 4g-4l) were designed and synthesized based on the chemical scaffolds of perampanel, hydantoins, progabide and etifoxine as anti-convulsant agents. The chemical structures of the synthesized compounds were confirmed by FT-IR, 1H NMR and 13C NMR spectroscopy. Anti-convulsant effect of the compounds was examined through intraperitoneal pentylenetetrazol (i.p. PTZ) induced epilepsy mouse models. Compound 4h (4-(4-bromo-benzyl)- 4 H-benzo[b] [1,4] thiazin-3(4 H)-one) demonstrated a promising activity toward chemically-induced seizure experiment. Molecular dynamics simulation on GABA-Aergic receptors as a plausible mechanism were also done to achieve the binding and orientation of compounds in the active site of the target to evaluate the results of docking and experimental studies. The computational results were confirmed the biological activity. DFT study of 4c and 4h was performed on B3LYP/6-311 G** level of theory. Reactivity descriptors such as HOMO, LUMO, electron affinity, ionization potential, chemical potential, hardness and softness were studied in detail and show that 4h has higher activity than 4c. Also, the frequency calculations were performed on the same level of theory and the results are in line with experimental data. Moreover, in silico ADMET properties were done to establish a relationship between the physiochemical data of the designed compounds and their in-vivo activity. Appropriate plasma protein binding and high blood-brain barrier penetration are the main features of desired in-vivo performance.