Novel 4-nitroimidazole analogues: synthesis, in vitro biological evaluation, in silico studies, and molecular dynamics simulation.

A new series of 4-nitroimidazole bearing aryl piperazines 7-16, tetrazole 17 and 1,3,4-thiadiazole 18 derivatives was synthesized. All derivatives were screened for their anticancer activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562, and Z138). Compound 17 proved the most potent compound of the series inhibiting proliferation of most of the selected human cancer cell lines with IC50 values in the low micromolar range. In addition, compound 11 exhibited IC50 values ranging 8.60-64.0 µM against a selection of cancer cell lines. These findings suggest that derivative 17 can potentially be a new lead compound for further development of novel antiproliferative agents. Additionally, 17-18 were assessed for their antibacterial and antituberculosis activity. Derivatives 17 and 18 were the most potent compounds of this series against both Staphylococcus aureus strain Wichita and a methicillin resistant strain of S. aureus (MRSA), as well as against Mycobacterium tuberculosis strain mc26230. The antiviral activity of 7-18 was also evaluated against diverse viruses, but no activity was detected. The docking study of compound 17 with putative protein targets in acute myeloid leukemia had been studied. Furthermore, the molecular dynamics simulation of 17 and 18 had been investigated.

Design, Synthesis, Docking Studies and Molecular Dynamics Simulation of New 1,3,5-Triazine Derivatives as Anticancer Agents Selectively Targeting Pancreatic Adenocarcinoma (Capan-1).

On the basis of remarkable anticancer profile of s-triazine nucleus, a new series of 2-methoxy-4-(3-morpholino-5-(arylamino)phenoxy)benzaldehyde derivatives 11 a-u was prepared and evaluated for in vitro antiproliferative activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562 and Z138). Compounds 11 o, 11 r and 11 s were the most potent anticancer agents on pancreatic adenocarcinoma (Capan-1) cell line with IC50 value of 1.4, 5.1 and 5.3 µM, respectively, while compounds 11 f, 11 g, 11 k, 11 l and 11 n displayed selective activity against the pancreatic adenocarcinoma (Capan-1) cell line with IC50 values of 7.3-11.5 µM. These results indicate that derivative 11 o may serve as a promising lead compound for the ongoing development of novel antiproliferative agents. The docking studies were conducted to predict the interactions of derivative 11 o with putative protein targets in pancreatic adenocarcinoma (Capan-1) cell line, specifically the prenyl-binding protein PDEδ. Furthermore, the analysis of the molecular dynamics simulation results demonstrated that complex 11 o promoted a higher stability to the prenyl-binding protein PDEδ.

Nonlinear Optical Properties and All Optical Switching of Curcumin Derivatives.

In this work OR1(E1,6E) -1,7-bis (4-propyloxy phenyl) hepta-1,6-diene-3,5 dione compound is synthesized. The compound has been characterized via computational technique by studying the molecule's electronic structures through calculating its HOMO and LUMO energies, and its band gap energy (EHOMO-ELUMO). The nonlinear refractive index (NLRI) of the solution of OR1 compound in DMF solvent is determined using diffraction patterns (DPs) which resulted when a continuous wave laser beam of wavelength 473 nm traversed the compound solution in a glass cell of 1 mm thickness. By counting the number of rings under maximum beam input power, the NLRI of value 10- 6 cm2/W resulted. The NLRI is calculated once more via the Z-scan technique and a value of 0.25 × 10- 7 cm2/W is obtained. The vertical convection current in the OR1 compound solution appears to be responsible for the asymmetries noticed in the DPs. The temporal variation of each DP is noticed together with the evolution of DPs against beam input power. DPs are numerically simulated based on the Fresnel-Kirchhoff integral with good accord compared to the experimental findings. Dynamic and static all-optical switching in the OR1 compound using two laser beams (473 and 532 nm) is tested successfully.

Curcumin Analogue Spectral, Nonlinear Optical Properties and All-optical Switching Using Visible, Low Power Cw Laser Beams.

In this study, we conducted the synthesis and diagnosis of compound denoted as 1A3, specifically, (2E,4E,9E,11E)-7-chloro-2,12-diphenyltrideca-2,4,9,11-tetraene-6,8-dione. The photoluminescent and UV-vis spectral properties of this compound are investigated. The compound is dissolved in both chloroform and DMF for analysis purposes. Compound 1A3's nonlinear optical (NLO) characteristics when dissolved in DMF, are extensively studied through a series of experiments including diffraction patterns (DPs) and Z-scan. The optical limiting (OL) property of the 1A3 compound is tested and a threshold value of 12.4 mW at the wavelength 473 nm is obtained. Additionally, we explored its potential for all-optical switching utilizing two low-power visible laser beams. Notably, we achieved a significant nonlinear refractive index (NLRI) reaching up to 5.921 x 10-11 m2/W. To analyze the obtained diffraction patterns, we employed the Fresnel-Kirchhoff integral equation and conducted meticulous simulations. The numerical outcomes showed satisfactory agreement with the experimental observations.

A novel pregnene analogs: synthesis, cytotoxicity on prostate cancer of PC-3 and LNCPa-AI cells and in silico molecular docking study.

New pregnene analogs of N-hydroxamic acid 6, imino-propane hydrazides 7 and 8 as well as the aryl amides 9-11, oxadiazole, pyrazole and sulfinyl analogs 13-15, via the hydrazide analog 5 of methyl ((5-pregnen-3ß,17ß-diol-15α-yl)thio)propanoate (4) were synthesized. The in vitro cytotoxic activities of selected synthesized steroids against two human prostate cancer cell lines (PC-3, and LNCaP-AI) were evaluated by MTT assay. Compound 10 was the most active cytotoxic agent among these steroids against PC-3 and LNCaP-AI cell lines with inhibition of 96.2%, and 93.6% at concentration levels of 10.0 µM and 91.8%, and of 79.8% at concentration of 1.0 µM, respectively. Molecular docking study of 10 showed a hydrogen bonding with the amino acid Asn705 residue of the receptor 1E3G, together with hydrophobic interactions. Therefore, compound 10 can be considered as a promising anticancer agent due to its potent cytotoxic activity.

Synthesis, Aromatase Inhibitory, Antiproliferative and Molecular Modeling Studies of Functionally Diverse D-Ring Pregnenolone Pyrazoles.

BACKGROUND: Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormonedependent breast cancer. Design of new steroidal aromatase inhibitors becomes imperative. OBJECTIVE: Synthesis and biological evaluation of two classes of structurally and functionally diverse D-ring pregnenolone pyrazoles as type I aromatase inhibitors and antiproliferative agents. METHODS: Pregnenolone (1) was converted to 3ß-hydroxy-21-hydroxymethylidenepregn-5-en-20-one (2), which upon cyclization with phenylhydrazine generated regioisomeric pairs of pyrazoles 4 and 5. Further, Knoevenagel condensation of pregnenolone (1) with 3-oxo-3-phenylpropanenitrile (6) produced 2-benzoyl-3-(3b-hydroxyandrostan- 5-ene-20-ylidene)-but-2-enenitrile (7), which upon cyclization with hydrazine or phenylhydrazine generated the pyrazoles 8 and 9. All new steroidal derivatives were tested for their aromatase inhibition activity using Dibenzylfluorescein (DBF) based fluorescence assay developed by Stresser et al. Antiproliferative activities were measured using Sulforhodamine B assay. The activities were promising and there was a coherence between aromatase inhibitory and antiproliferative activities. RESULTS: The study reveals the immense potential of pregnenolone pyrazoles as aromatase inhibitors for the treatment of breast cancer. Molecular docking studies proved efficient binding of the new steroidal analogs on human placental aromatase. CONCLUSION: In the overall study, most of the compounds exhibited potential activity for the treatment of hormone dependent breast cancer. Compounds 4c and 4d were found to be the most promising pharmacons. Furthermore, compounds 4c and 4d were applied for their molecular docking study on human placental aromatase to predict their possible binding modes with the enzyme. These studies revealed that such molecules have high scope and potential for further investigation towards the treatment of estrogen dependent breast cancer.

The nonlinear optical properties of two dihydropyridones derived from curcumin.

Two dihydropyridone compounds are synthesized from curcumin using microwave radiation. Both compounds were identified by their melting points and 1HNMR spectra. The nonlinear properties viz., nonlinear absorption coefficients and nonlinear refractive index of both compounds were calculated at wavelength 473 nm using the diffraction ring patterns and Z-scan techniques separately. The diffraction ring patterns evolved from circular symmetric to asymmetric due to convection current in the vertical direction. As a result of using Gaussian laser beam, the Fraunhofer approximation of the Fresnel-Kirchhoff diffraction, have led to successful simulation of the diffraction ring patterns with good quantitative and excellent qualitative agreements compared with experimental results. Optical limiting property has been tested in both compounds.

One-bond 1 J(15 N,H) coupling constants at sp2 -hybridized nitrogen of Schiff bases, enaminones and similar compounds: A theoretical study.

1 J(15 N,H) coupling constants for enaminones and NH-forms of intramolecularly hydrogen-bonded Schiff bases as model compounds for sp2 -hybridized nitrogen atoms are evaluated using density functional theory (DFT) to find the optimal functionals and basis sets. Ammonia is used as a test molecule and its one-bond coupling constant is compared with experiment. A methylamine Schiff base of a truncated molecule of gossypol is used for checking the performance of selected B3LYP, O3LYP, PBE, BHandH, and APFD density functionals and standard, modified, and dedicated basis sets for coupling constants. Both in vacuum and in chloroform, modeled by the simple continuum model of solvent, the modified basis sets predict significantly better the 1 J(15 N,H) value in ammonia and in the methylamine Schiff base of a truncated molecule of gossypol than the standard basis sets. This procure is then used on a broad set of intramolecularly hydrogen-bonded molecules, and a good correlation between calculated and experimental one-bond NH coupling constants is obtained. The 1 J(15 N,H) couplings are slightly overestimated. The calculated data show for hydrogen-bonded NH interatomic distances that the calculated values depend on the NH bond lengths. The shorter the bond lengths, the larger the 1 J(15 N,H). A useful correlation between 1 J(15 N,H) and NH bond length is derived that enables realistic predictions of one-bond NH coupling constants. The calculations reproduce experimentally observed trends for the studied molecules.

Strong intramolecular hydrogen bonds and steric effects involving C═S groups: An NMR and computational study.

A number of 5-acyl rhodanines and thiorhodanines with bulky acyl groups (pivaloyl and adamantoyl), not previously available, have been synthesized. The compounds are shown to exist in the enol form. Structures have been calculated using both the MP2 approach and the B3LYP-GD3BJ functional and the 6-311++G(d,p) basis set. Hydrogen bond energies are estimated by subtracting energies of a structure with the OH group turned 180° from those of the intramolecularly hydrogen-bonded one. Properties such as OH chemical shifts, two-bond isotope effects on 13 C chemical shifts, electron densities at the bond critical point from atoms in molecules analysis, and the hydrogen bond energies show that the sterically hindered compounds have stronger hydrogen bonds than methyl or isopropyl derivatives. The combination of oxygen and sulfur derivatives enables a detailed analysis of hydrogen bond energies.

Intramolecular Hydrogen Bonds in Normal and Sterically Compressed o-Hydroxy Aromatic Aldehydes. Isotope Effects on Chemical Shifts and Hydrogen Bond Strength.

A number of o-hydroxy aromatic aldehydes have been synthesized to illustrate the effect of steric compression and O···O distances on the intramolecular hydrogen bond and the hydrogen bond energies. Hydrogen bond energies have been calculated using the 'hb and out' method using either the MP2 method or the B3LYP functional with the basis set 6-311++G(d,p). However, several compounds cannot be treated this way. Hydrogen bond energies are also determined using electron densities at bond critical points and these results are in good agreement with the results of the 'hb and out' model. Two-bond deuterium isotope effects on 13C chemical shifts are suggested as an experimental way to obtain information on hydrogen bond energies as they easily can be measured. Isotope effects on aldehyde proton chemical shifts have also been measured. The former show very good correlation with the hydrogen bond energies and the latter are related to short O···O distances. Short O···O distances can be obtained as the result of short C=C bond lengths, conjugative effects, and steric compression of the aldehyde group. Short O···O distances are in general related to high hydrogen bond energies in these intramolecularly hydrogen-bonded systems of resonance assisted hydrogen bond (RAHB) type.

Formation and temporal evolution of diffraction ring patterns in a newly prepared dihydropyridone.

A dihydropyridone has been prepared from butylamine and curcumin. A theoretical DFT study was conducted to determine the most stable conformer of the studied molecule (among three conformers) using the B3LYP/6-311+G(d,p) level of theory. This is assisted by the prediction of the 13C NMR chemical shifts of the conformers which then correlated with the observed 13C NMR chemical shifts. A TD-DFT study was conducted to analyze the electronic spectrum of the most stable conformer in order to determine the transitions responsible for the longer band in the electronic spectrum of the molecule. As well the frontier orbitals in the most stable conformer were analyzed to establish the density of donor and acceptor sites in the molecule that may be responsible for the nonlinear optical (NLO) properties of the studied molecule. Diffraction ring patterns were observed as a result of the use of visible, 473 nm, low power single mode laser beam traversed a thin cell containing solution of dihydropyridone. The nonlinear refractive index, n2, was determined based on the number of diffraction rings per a pattern observed and by the Z-scan technique and both results are compared. The upward convection heat effect appears to be responsible for the asymmetries observed in the diffraction ring patterns. The use of convergent and divergent laser beams has led to new types of diffraction ring patterns. Temporal evolution of each diffraction ring patterns was registered. The diffraction ring patterns experimentally obtained are numerically calculated using the Fresnel-Kirchhoff diffraction integral, with good qualitative and reasonable quantitative agreements.

NMR, MP2, and DFT study of thiophenoxyketenimines (o-thio-Schiff bases): Determination of the preferred form.

Five new thiophenoxyketinimines have been synthesized. 1 H and 13 C NMR spectra as well as deuterium isotope effects on 13 C chemical shifts are determined, and spectra are assigned. DFT and MP2 calculations of both structures, chemical shifts, and isotope effects on chemical shifts are done. The combined analysis reveals that the compounds are primarily on a zwitterionic form with an NH+ and a S- group and with a little of the neutral form mixed in. Very strong intramolecular hydrogen bonding is found and very high NH chemical shifts are observed. The theoretical calculations show that calculations at the MP2 level are best to obtain correct "C═S" chemical shifts.

Hepatitis B and C virus prevalence in couples attending an in vitro fertilization clinic in a tertiary care hospital in Saudi Arabia: comparison with ten years earlier.

BACKGROUND: Viral hepatitis B (HBV) and C (HCV) are a major public health problem in Saudi Arabia. Recent data has indicated a major reduction in viral hepatitis prevalence in Saudi population. However, there is limited data for infertile Saudi couples. OBJECTIVES: To determine the prevalence of HCV and HBV attending an in vitro fertilization (IVF) clinic in Saudi Arabia between 2012 and 2015 to compare with the prevalence 10 years earlier in the same center. DESIGN: Retrospective prevalence study. SETTING: Tertiary care center in Riyadh. PATIENTS AND METHODS: Data on the prevalence of HBV and HCV was collected on all couples seen at the IVF unit between 2002-2005 and 2012-2015. MAIN OUTCOME MEASURE(S): Prevalence of HBV and HCV. RESULTS: In 4442 patients during 2002-2005 and 5747 patients during 2012-2015, the prevalence of HBV was significantly less in 2012-2015 compared with 2002-2005 (1.67% [97 patients] vs 4.7% [210 patients], P < .0001), respectively, but HCV prevalence was similar for the two periods (0.7% for both periods) (P=.887). The hepatitis B seroprevalence rate was higher in males compared to females during 2002-2005 (6.3% vs 3.1%) (P < .0001) and 2012-2015 (2.4% vs 1.1% ) (P < .0001), respectively. CONCLUSION: The significant drop in HBV prevalence was most likely due to the introduction of the vaccination program in 1989, while reasons for HCV prevalence remaining unchanged are unclear. LIMITATION: No data on confounding factors that may have affected the prevalence.

Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines.

BACKGROUND: Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. MATERIAL AND METHODS: Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC50 values and binding energies. RESULTS: The compounds displayed IC50 values between 0.7±0.03 and 20.2±0.25µM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from -9.00±0.10 to -6.20±0.02kcal/mol and pKi values from 0.24±0.04 to 29.17±0.88µM. At the ATP-binding site of P-gp, lowest binding energies ranged from -9.78±0.17 to -6.79±0.01kcal/mol and pKi values from 0.07±0.02 to 0.03±0.03µM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF-CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R=0.797 and R=0.794 for training and test sets). CONCLUSION: Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR.

New biaryl-chalcone derivatives of pregnenolone via Suzuki-Miyaura cross-coupling reaction. Synthesis, CYP17 hydroxylase inhibition activity, QSAR, and molecular docking study.

A new class of steroids is being synthesized for its ability to prevent intratumoral androgen production by inhibiting the activity of CYP17 hydroxylase enzyme. The scheme involved the synthesis of chalcone derivative of pregnenolone 5 which was further modified to the corresponding biaryl-chalcone pregnenolone analogs 16-25 using Suzuki-Miyaura cross-coupling reaction. The synthesized compounds were tested for activity using human CYP17α hydroxylase expressed in Escherichia coli. Compounds 21 was the most active inhibitor in this series, with IC50 values of 0.61µM and selectivity profile of 88.7% inhibition of hydroxylase enzyme. Molecular docking study of 21 was performed and showed the hydrogen bonds and hydrophobic interaction with the amino acid residues of the active site of CYP17.

A new pregnenolone analogues as privileged scaffolds in inhibition of CYP17 hydroxylase enzyme. Synthesis and in silico molecular docking study.

A new series of 17-(N-(arylimino)-5-pregnen-3ß-ol derivatives 19-32 as well as carboxylate and acrylate analogues of pregnenolone 37-40 were synthesized and evaluated for their inhibitory activity against human CYP17 hydroxylase expressed in Escherichia coli. Compounds 32 and 37 were the most potent analogues in this series, showing inhibition activity with IC50 = 2.11 and 1.29 µM, respectively. However, the analogue 37 revealed a better selectivity profile (83.21% inhibition of hydroxylase), which is a leading candidate for further development. Molecular docking study of 37 showed binding with the amino acid residues of CYP17 through hydrogen bonds and hydrophobic interaction.

New CYP17 hydroxylase inhibitors: synthesis, biological evaluation, QSAR, and molecular docking study of new pregnenolone analogs.

A new series of pregnenonlone analogs were synthesized and evaluated for their inhibitory activity against cytochrome P450 (CYP17 hydroxylase enzyme). In general, the 5-aryl-1,3,4-thiadiazol-2-yl)-imino-pregnenolone derivatives 11-15 were more active than the sulfonate 24-31 and the ester 37-41 analogs. Derivative 12 showed optimal activity in this series, with IC50 values of 2.5 µM compared with the standard abiraterone (IC50 = 0.07 µM). However, the analogs 11 and 25 showed a better selectivity profile (81.5 and 82.7% inhibition of hydroxylase, respectively), which may be a useful lead in CYP17 inhibition studies. Molecular docking studies demonstrated quite similar binding patterns of all new pregnenolone derivatives at the active site of CYP17 through hydrogen bonding and hydrophobic interaction.

Synthesis and evaluation of antioxidant and antibacterial activities of new substituted bis(1,3,4-oxadiazoles), 3,5-bis(substituted) pyrazoles and isoxazoles.

Two series of five membered heterocyclic bis(1,3,4-oxadiazole) derivatives 2(a-h) and 3,5-bis(substituted)pyrazoles, isoxazoles 3(a,b,d-i), 4(a-c) were synthesized via oxidative cyclization of some diaroylhydrazones using chloramine-T and cyclocondensation reaction with hydrazine hydrate and hydroxylamine hydrochloride, respectively. The newly synthesized compounds were screened for antioxidant and anti-microbial activities. Compounds 2(b), 3(b), and 4(a) showed higher antioxidant activity at 10 µg/ml while compounds 2(a), 3(a), 3(f), and 4(a) exhibited better anti-microbial activity at 100µg/ml compared with standard vitamin C and ciprofloxacin, respectively. Structures of newly synthesized compounds were confirmed by elemental analysis and spectral IR, (1)H NMR, and (13)C NMR data.

Microwave-assisted synthesis of novel 2,3-dihydro-4-pyridinones.

Novel 2,3-dihydro-4-pyridinones were synthesized via the reaction of curcumin and primary amines or amine acetates under microwave irradiation. Montmorillonite K-10 was used as a catalyst. Reaction times did not exceed 120 s. The structures of the compounds were established by elemental analysis and from their mass, 1H- and 13C-NMR spectra.

Synthesis of symmetrical and non-symmetrical diimines from dimedone.

Symmetrical and non-symmetrical diimines derived from dimedone were synthesized by the reaction of their corresponding enaminothiones with primary amines. The synthesized compounds were characterized using micro analytical data and NMR spectroscopy. Theoretical calculations by B3LYP/6-31G(d,p) level of theory show that the enolic form is the most stable within the possible tautomeric forms of the compounds.