Two new series of oxadiazole and pyrazoline derivatives were designed and synthesized as promising EGFR-TK inhibitors. The in vitro antiproliferative activity was studied against three human cancer cell lines; HCT116, HepG-2 and MCF7 using MTT assay. Compound 10c showed the most potent anticancer activity against all cancer cell lines, with IC50 range of 1.82 to 5.55 μM, while proving safe towards normal cells WI-38 (IC50 = 41.17 μM) compared to the reference drug doxorubicin (IC50 = 6.72 μM). The most active candidates 5a, 9b, 10a, 10b and 10c were further assessed for their EGFR-TK inhibition. The best of which, compounds 5a and 10b showed IC50 of 0.09 and 0.16 μM respectively compared to gefitinib (IC50 = 0.04 μM). Further investigation against other EGFR family members, showed that 5a displayed good activities against HER3 and HER4 with IC50 values 0.18 and 0.37 µM, respectively compared to gefitinib (IC50 = 0.35 and 0.58 µM, respectively). Furthermore, 5a was evaluated for cell cycle distribution and apoptotic induction on HepG-2 cells. It induced mitochondrial apoptotic pathway and increased accumulation of ROS. Molecular docking study came in agreement with the biological results. Compounds 5a and 10b showed promising drug-likeness with good physicochemical properties.

A simple pyrazoline-based \'\'turn off\'\' fluorescent sensor 5-(4-methoxyphenyl)-3-(5-methylfuran-2-yl)-1-phenyl-4,5-dihydro-1H-pyrazole (PFM) was synthesized and well characterized by different techniques such as FT-IR, 1H-NMR, 13C-NMR, and mass spectrometry. The synthesized sensor PFM was utilized for the detection of Fe3+ ions. Fluorescence emission selectively quenched by Fe3+ ions compared to other metal ions (Mn2+, Al3+, Fe2+, Hg2+, Cu2+, Co2+, Ni2+, Cd2+, Pb2+, and Zn2+) via paramagnetic fluorescence quenching and showed good anti-interference ability over the existence of other tested metals. Under optimum conditions, the fluorescence intensity of sensor quenched by Fe3+ in the range of 0 to 3 μM with detection limit of 0.12 μM. Binding of Fe3+ ions to PFM solution were studied by fluorescent titration, revealed formation of 1:1 PFM-Fe metal complex and binding constant of complex was found to be of 1.3 × 105 M-1. Further, the fluorescent sensor has been potentially used for the detection of Fe3+ in environmental samples (river water, tap water, and sewage waste water) with satisfactory recovery values of 99-101%.

The present study illustrates the design and synthesis of new series of 3-trifluoromethylpyrazole tethered chalcone-pyrrole and pyrazoline-pyrrole derivatives. All compounds were further screened for in vitro cytostatic activities on full NCI 60 cancer cell lines at National Cancer Institute, USA. Compounds (2E)-3-(1H-pyrrol-2-yl)-1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}prop-2-en-1-one (5a) and (2E)-1-{3-methyl-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-(1H-pyrrol-2-yl)prop-2-en-1-one (5c) displayed significant antiproliferative activity (Growth Percentage: -77.10 and -92.13, respectively at 10 μM concentration) against the UO-31 cell lines from renal cancer and were further selected for assay at 10-fold dilutions of five different concentrations (10-4 to 10-8  M). Both compounds 5a and 5c exhibited promising antiproliferative activity (GI50 : 1.36 to 0.27 μM) against leukemia cancer cell lines HL-60 and RPMI-8226, colon cancer cell lines KM-12; breast cancer cell lines BT-549. Moreover, both compounds 5a and 5c were found to be non-cytotoxic (LC50 >100) against HL-60, RPMI-8226, and KM-12 cell lines. Remarkably, GI50 values of compounds 5a and 5c were identified as more promising than sunitinib against most cancer cell lines. In silico study of compounds 5a and 5c exemplified the desired ADME properties for drug-likeness as well as tighter interactions with VEGFR-2. Hence, compounds 5a and 5c would be good cytotoxic agents after further clinical study.

The present paper is a continuation of comprehensive study regarding to synthesis and properties of pyrazoles and their derivatives. In its framework an experimental and theoretical studies of thermal decomposition of the 3,3-diphenyl-4-(trichloromethyl)-5-nitropyrazoline were performed. It was found, that the decompositions of the mentioned pyrazoline system in the solution and at the melted state proceed via completely different molecular mechanisms. These mechanisms have been explained in the framework of the Molecular Electron Density Theory (MEDT) with the computational level of B3LYP/6-31G(d). A Bonding Evolution Theory (BET) examination of dehydrochlorination of the 3,3-diphenyl-4-(trichloromethyl)-5-nitropyrazoline permits elucidation of the molecular mechanism. It was found, that on the contrary for most known HCl extrusion processes in solution, this reaction is realised via single-step mechanism.

BACKGROUND: The frequent use of antibacterial agents leads to antimicrobial resistance, which is one of the biggest threats to global health today. Therefore, the discovery of novel antimicrobial agents is still urgently needed to overcome the severe infections caused by these putative pathogens resistant to currently available drugs.
OBJECTIVE: The present work was aimed to synthesize and investigate the preliminary structureactivity relationships (SARs) of isoxazoline and pyrazoline derivatives as antimicrobial agent.
METHODS: Target compounds were obtained in a multistep reaction synthesis and the antimicrobial activity was investigated in several species; two-gram negative (Escherichia coli and Pseudomonas aeruginosa), two-gram positive (Staphylococcus aureus and Bacillus subtilis) and one fungi (Candida albicans), using cup-plate agar diffusion method. The most potent compounds were docked into glucosamine-6-phosphate synthase (GlcN-6-P), the molecular target enzyme for antimicrobial agents, using Autodock 4.2 program.
RESULTS: Herein, thirteen novel target compounds were synthesized in moderate to good isolated yield. Based on the SARs, two compounds (2c and 5c) were found to be potent antimicrobial agents on all tested targets, recording potency higher than amoxicillin, the standard antimicrobial drug. Compound 2b identified as selective for gram-negative, while compound 7a found to be selective for gram-positive. The hit compounds (2c, 5a, 5c and 5d) were subjected to a docking study on glucosamine-6-phosphate synthase (GlcN-6-P). All hits were found to bind to the orthosteric (active) site of the enzyme, which might represent a competitive mechanism of inhibition.
CONCLUSIONS: The newly synthesized heterocyclic compounds could serve as potent leads for the development of novel antimicrobial agents.

A series of pyrazole-pyrazoline substituted with benzenesulfonamide were synthesized and evaluated for their antimalarial activity in vitro and in vivo. The compounds were active against both chloroquine (CQ) sensitive (3D7) and CQ resistant (RKL-9) strains of Plasmodium falciparum. Seven compounds (7e, 7i, 7j, 7l, 7m, 7o and 7p) exhibiting EC50 less than 2 μM. A mechanistic study of compound 7o revealed that these compound act through the inhibition of β-hematin. The study indicated that these compounds can serve as lead compounds for further development of potent antimalarial drugs.

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbaldehyde have been investigated experimentally and theoretically. The title compound was optimized using at HF and DFT levels of calculations. The B3LYP/6-311++G(d,p) (5D,7F) results and in agreement with experimental infrared bands. The normal modes are assigned using potential energy distribution. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using natural bonding orbital analysis. The frontier molecular orbital analysis is used to determine the charge transfer within the molecule. From molecular electrostatic potential map, it is evident that the negative electrostatic potential regions are mainly localized over the carbonyl group and mono substituted phenyl ring and are possible sites for electrophilic attack and, positive regions are localized around all para substituted phenyl and pyrazole ring, indicating possible sites for nucleophilic attack. First hyperpolarizability is calculated in order to find its role in nonlinear optics. The geometrical parameters are in agreement with experimental data. From the molecular docking studies, it is evident that the fluorine atom attached to phenyl ring and the carbonyl group attached to pyrazole ring are crucial for binding and the results draw us to the conclusion that the compound might exhibit phosphodiesterase inhibitory activity.

3-Naphthyl-1-phenyl-5-(5-fluoro-2-nitrophenyl)-2-pyrazoline (NPFP), a fluorogenic probe and its derivative NPFP-Phenylephrine were synthesized and their absorption and fluorescence properties were recorded in solvents of varying polarity. Spectroscopic studies reveal that, the solvatochromic behavior of the compounds depend not only on the polarity but also on the hydrogen-bonding properties of the solvents. The effects of β-cyclodextrin on the fluorescence properties of both compounds were studied. It was found that there is an enhancement in the fluorescence intensity of labeled drug (NPFP-Phenylephrine) in the presence of β-cyclodextrin. In the present study, the molecular motions of NPFP-Phenylephrine embedded in a β-cyclodextrin cavity have been investigated by fluorescence techniques in steady-state and time resolved modes.

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 1-[3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]ethanone have been investigated experimentally and theoretically. The geometrical parameters are in agreement with XRD data. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. From the MEP it is evident that the negative charge covers the carbonyl group and the positive region is over the remaining groups. The more electronegativity in the carbonyl group makes it the most reactive part in the molecule. First hyperpolarizability is calculated in order to find its role in nonlinear optics. From the molecular docking studies, it is evident that the fluorine atom attached to benzene ring and ethanone attached to the pyrazoline ring are crucial for binding and the compound might exhibit inhibitory activity against TPII and may act as anti-neoplastic agent.

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 1-[5-(4-bromophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]ethanone have been investigated experimentally and theoretically using Gaussian09 software package. The title compound was optimized using the HF/6-31G(d) (6D, 7F), B3LYP/6-31G (6D, 7F) and B3LYP/6-311++G(d,p) (5D, 7F) calculations. The B3LYP/6-311++G(d,p) (5D, 7F) results and in agreement with experimental infrared bands. The geometrical parameters are in agreement with XRD data. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. Molecular electrostatic potential was also performed. From the MEP it is evident that the negative charge covers the C=O group and the positive region is over the rings. First hyperpolarizability is calculated in order to find its role in nonlinear optics. Molecular docking studies suggest that the compound might exhibit inhibitory activity against TPII and may act as anti-neoplastic agent.