Design, Synthesis, Molecular Docking, Dynamics and in vitro Evaluation of Novel 2-substituted-1-hydroxyethane-1, 1-bis(phosphonic acid) Derivatives as Human Farnesyl Pyrophosphate Synthase Inhibitors with Expected Anticancer Activity.

BACKGROUND: Nitrogenous bisphosphonates (NBPs) are the major class of drugs that are used to treat osteoporosis. Recently, bisphosphonates (BPs) were reported to have an anticancer effect. These agents feature a high affinity that enables them to bind strongly to the human farnesyl pyrophosphate synthase enzyme. The correlation between this affinity and their anticancer effect was confirmed. OBJECTIVE: To date, the use of an oxygen atom as an isosteric replacement for the electronegative nitrogen atom in NBPs has not been reported, and its ability to retain the linker length and bisphosphonate pharmacophore remains unknown. The main aim of this work was to design some isosteric bisphosphonate analogs with oxygen atoms and evaluation of their binding affinity and anticancer activity. METHODS: The binding mode and stability of the designed compounds were achieved using human farnesyl pyrophosphate synthase (HFPPS) by docking and dynamic simulations. The compounds were synthesized, characterized, and screened for their anticancer activity against the breast cancer MCF-7 cell line and lung cancer A-549 cell line. The inhibitory activity of the tested compounds against HFPPS was evaluated. RESULTS: The compounds under investigation showed potential anticancer activity against the lung cell line with IC50 values of 41.7, 47.4, and 34.8 µg/ml in comparison to that of Risedronic acid (115 µg/ml). However, they do not exhibit potential activity against the breast cancer cell line. CONCLUSION: Compounds VII and VIII showed in vitro inhibition of human farnesyl pyrophosphate synthase with IC50 values of 82.2 and 98.8 µg/ml, respectively. Further optimization may be required in the future.

Antiestrogenic Activity and Possible Mode of Action of Certain New Nonsteroidal Coumarin-4-acetamides.

The preparation of certain 2-(2-oxo-2H-chromen-4-yl)-N-substituted acetamides IIIa-h was planned as a step in the development of new modified nonsteroidal antiestrogens. The purity of target compounds IIIa-h was checked by thin-layer chromatography (TLC), and their structures were confirmed using various spectroscopic tools including IR, 1H-NMR, 13C-NMR, and MS spectroscopy. Viability tests were applied using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to evaluate the cytotoxic effect of the synthesized compounds against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compound IIIb proved the most active against MCF-7 cells, with an IC50 value of 0.32 µM. The results of an analysis of in vitro antiestrogenic activity indicated that only compound IIIb exhibited antiestrogenic activity; its IC50 value of 29.49 µM was about twice as potent as that of the reference compound, MIBP. The aromatase activity was evaluated for the synthesized target compounds IIIa-g and the intermediates Ib and IIa. A significant aromatase inhibition was observed for the intermediate Ib and compound IIIe, with IC50 values of 14.5 and 17.4 µM, respectively. Compound IIIb, namely 7-methoxy-4-(2-oxo-2-(piperidin-1-yl)ethyl)-2H-chromen-2-one, could be used as an antiestrogen and/or cytotoxic agent with selective activity against tumor cells.

New Isatin-Indole Conjugates: Synthesis, Characterization, and a Plausible Mechanism of Their in vitro Antiproliferative Activity.

BACKGROUND: Cancer remains the leading cause of human morbidity universally. Hence, we sought to assess the in vitro antiproliferative activity of new isatin-based conjugates (5a-s) against three human cancer cell lines. METHODS: The antiproliferative activities of compounds 5a-s were evaluated in vitro and their ADME (absorption, distribution, metabolism and excretion) was carried out using standard protocols. Subsequently, Western blot analysis was conducted to elucidate the potential antiproliferative mechanism of compounds 5a-s. RESULTS: The in vitro antiproliferative activities of compounds 5a-s against the tested cancer cell lines ranged from 20.3 to 95.9%. Compound 5m had an IC50 value of 1.17 µM; thus, its antiproliferative potency was approximately seven-fold greater than that of sunitinib (IC50 = 8.11 µM). In-depth pharmacological testing was conducted with compound 5m to gain insight into the potential antiproliferative mechanism of this class of compounds. Compound 5m caused an increase in the number of cells in the G1 phase, with a concomitant reduction of those in the G2/M and S phases. Additionally, compound 5m significantly and dose-dependently reduced the amount of phosphorylated retinoblastoma protein detected. Compound 5m enhanced expression of B cell translocation gene 1, cell cycle-associated proteins (cyclin B1, cyclin D1, and phosphorylated cyclin-dependent kinase 1), and a pro-apoptotic protein (Bcl-2-associated X protein gene), and activated caspase-3. ADME predictions exposed the oral liability of compounds 5a-s. CONCLUSION: Herein, we revealed the antiproliferative activity and ADME predictions of the newly-synthesized compounds 5a-s and provided a detailed insight into the pharmacological profile of compound 5m. Thus, compounds 5a-s can potentially be exploited as new antiproliferative lead compounds for cancer chemotherapeutic.

Antiproliferative activity and possible mechanism of action of certain 5-methoxyindole tethered C-5 functionalized isatins.

BACKGROUND: Cancer is one of the most dreaded human diseases, that has become an ever-increasing health problem and is a prime cause of death globally. The potential antiproliferative activity of certain indole-isatin molecular hybrids 5a-w was evaluated in vitro against three human cancer cell lines. METHODS: Standard protocols were adopted to examine the antiproliferative potential and mechanisms of compounds 5a-w. Western blot analysis was carried out on compound 5o. RESULTS: Compounds 5a-w demonstrated in vitro antiproliferative activity in the range of 22.6-97.8%, with compounds 5o and 5w being the most active antiproliferative compounds   with IC50 values of 1.69 and 1.91 µM, which is fivefold and fourfold more potent than sunitinib (IC50=8.11 µM), respectively. Compound 5o was selected for in-depth pharmacological testing to understand its possible mechanism of antiproliferative activity. It caused a lengthening of the G1 phase and a reduction in the S and G2/M phases of the cell cycle and had an IC50 value of 10.4 µM with the resistant NCI-H69AR cancer cell line. Moreover, compound 5o significantly decreased the amount of phosphorylated Rb protein in a dose-dependent fashion, which was confirmed via Western blot analysis. CONCLUSION: The current investigation highlighted the potential antiproliferative activity of compounds 5a-w as well as the antiproliferative profile of compound 5o. These compounds can be harnessed as new lead antiproliferatives in the preclinical studies of cancer chemotherapy.

QSAR-based rational discovery of novel substituted-4'-iminospiro[indoline-3,3'-[1,2,5]thiadiazolidinyl]-2-one 1',1'-dioxide with potent in vitro anticancer activity.

Recent studies have suggested that aldose reductase inhibition preferentially inhibits the growth of cancer cells. However, the investigations of this issue are not many. Novel nine substituted- 4'-iminospiro[indoline-3,3'-[1,2,5] thiadiazolidinyl]-2-one 1',1'-dioxide derivatives were designed by both isosteric replacement of the imidazolidine-2,5-dione moiety in spirohydantoin scaffold and conformational rigidification approaches. A QSAR with high predictive power (r2 = 0.99) was created from a series of potent aldose reductase inhibitors and was used to predict the activity of our new compounds. Compound 5 showed the best docking score (- 33.24 kcal/mol) with the least RMSD value (< 1.5) obtained by molecular dynamic simulations over 20 ns. All compounds showed promising anticancer activities especially compound 5 that achieved the highest inhibitory activities with IC50; 0.013, 0.031, 0.064, and 0.048 mmol/L against breast, colon, prostate, and lung cell lines respectively. The discovery of this lead compound confirmed the rational design. Further investigations may be required for optimization of this compound.

Synthesis, Spectroscopic Identification and Molecular Docking of Certain N-(2-{[2-(1H-Indol-2-ylcarbonyl) Hydrazinyl](oxo)Acetylphenyl)Acetamides and N-[2-(2-{[2-(Acetylamino)Phenyl](oxo)Acetylhydrazinyl)-2-Oxoethyl]-1H-Indole-2-Carboxamides: New Antimicrobial Agents.

N-(2-{[2-(1H-Indol-2-ylcarbonyl)hydrazinyl](oxo)acetyl}phenyl)acetamides (5a⁻h) and N-[2-(2-{[2-(acetylamino)phenyl](oxo)acetyl}hydrazinyl)-2-oxoethyl]-1H-indole-2-carboxamides (5i⁻l) were synthesized and characterized with different analytical tools. N-Acetylisatines 4a⁻d were subjected to ring opening at their C2 carbons with the aid of different indole-bearing hydrazides 3a,b and 7 to afford the respective glyoxylamides 5a⁻l. The antimicrobial activity of the target compounds 5a⁻l was assessed with the aid of Diameter of the Inhibition Zone (DIZ) and Minimum Inhibitory Concentration (MIC) assays against a panel of Gram-positive and Gram-negative bacteria and certain fungal strains. The antimicrobial screening revealed that Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans are the most sensitive microorganisms towards the synthesized compounds 5a⁻l. In addition, compounds 5c and 5h emerged as the most active congeners towards Staphylococcus aureus and Candida albicans, respectively. Molecular docking studies revealed the possible binding mode of compounds 5c and 5h to their target proteins.

Synthesis and biological evaluation of certain hydrazonoindolin-2-one derivatives as new potent anti-proliferative agents.

In connection with our research program on the development of novel indolin-2-one-based anticancer candidates, herein we report the design and synthesis of different series of hydrazonoindolin-2-ones 3a-e, 5a-e, 7a-c, and 10a-l. The synthesised derivatives were in vitro evaluated for their anti-proliferative activity towards lung A-549, colon HT-29, and breast ZR-75 human cancer cell lines. Compounds 5b, 5c, 7b, and 10e emerged as the most potent derivatives with average IC50 values of 4.37, 2.53, 2.14, and 4.66 µM, respectively, which are superior to Sunitinib (average IC50 = 8.11 µM). Furthermore, compounds 7b and 10e were evaluated for their effects on cell cycle progression and levels of phosphorylated retinoblastoma (Rb) protein in the A-549 cancer cell line. Moreover, 7b and 10e inhibited the cell growth of the multidrug-resistant lung cancer NCI-H69AR cell line with IC50 = 16 µM. In addition, the cytotoxic activities of 7b and 10e were assessed towards three non-tumorigenic cell lines (Intestine IEC-6, Breast MCF-10A, and Fibroblast Swiss-3t3) where both compounds displayed mean tumor selectivity index (1.6 and 1.8) higher than that of Sunitinib (1.4).

FT-IR and FT-Raman spectroscopic signatures, vibrational assignments, NBO, NLO analysis and molecular docking study of 2-{[5-(adamantan-1-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}-N,N-dimethylethanamine.

FT-Raman and FT-IR spectra of the title compound 2-{[5-(adamantan-1-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}-N,N-dimethylethanamine were recorded and investigated. The DFT/B3LYP/6-311++G(d,p) method was used to compute the vibrational wavenumbers. A good coherence between experimental and theoretical wavenumbers shows the preciseness of the assignments. NLO properties like the dipole moment, polarizability, first static hyperpolarizability, molecular electrostatic potential surface and contour map have been calculated to get a better cognizance of the properties of the title molecule. Natural bond orbital analysis has been applied to estimate the stability of the molecule arising from charge delocalization. The molecular docking studies concede that title compound may exhibit HIV-1 Protease 1N49 inhibitory activity.

Synthesis, docking and biological activities of novel hybrids celecoxib and anthraquinone analogs as potent cytotoxic agents.

Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl) amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2) have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src) and platelet-derived growth factor receptor, PDGFR (c-Kit). The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src).

FT-IR, FT-Raman, molecular structure, first order hyperpolarizability, HOMO and LUMO analysis, MEP and NBO analysis of 3-(adamantan-1-yl)-4-(prop-2-en-1-yl)-1H-1,2,4-triazole-5(4H)-thione, a potential bioactive agent.

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 3-(adamantan-1-yl)-4-(prop-2-en-1-yl)-1H-1,2,4-triazole-5(4H)-thione have been investigated experimentally and theoretically using Gaussian09 software package. Potential energy distribution of normal modes vibrations was done using GAR2PED program. The HOMO and LUMO analysis are used to determine the charge transfer within the molecule. The stability of the molecule arising from hyperconjugative interaction and charge delocalization has been analyzed using NBO analysis. The calculated geometrical parameters are in agreement with the XRD data. The calculated first hyperpolarizability is high and the title compound is an attractive candidate for further studies in nonlinear optical applications. To estimate the chemical reactivity of the molecule, the molecular electrostatic potential is calculated for the optimized geometry of the molecule.

In vitro anti-Candida activity of certain new 3-(1H-imidazol-1-yl)propan-1-one oxime esters.

Anti-Candida activities of certain new oximes 4a-d and their respective aromatic esters 5a-l are reported. The tested compounds 4a-d and 5a-l exhibited better anti-Candida profiles than fluconazole. Compound 5j, namely (E)-3-(1H-imidazol-1-yl)-1-phenylpropan-1-one O-4-chlorobenzoyl oxime emerged as the most active congener, with a MIC value of 0.0054 µmol/mL being more potent than both fluconazole (MIC > 1.6325 µmol/mL) and miconazole (MIC value = 0.0188 µmol/mL) as a new anti-Candida albicans agent.

1-Aryl-3-(1H-imidazol-1-yl)propan-1-ol esters: synthesis, anti-Candida potential and molecular modeling studies.

BACKGROUND: An increased incidence of fungal infections, both invasive and superficial, has been witnessed over the last two decades. Candida species seem to be the main etiology of nosocomial fungal infections worldwide with Candida albicans, which is commensal in healthy individuals, accounting for the majority of invasive Candida infections with about 30-40% of mortality. RESULTS: New aromatic and heterocyclic esters 5a-k of 1-aryl-3-(1H-imidazol-1-yl)propan-1-ols 4a-d were successfully synthesized and evaluated for their anti-Candida potential. Compound 5a emerged as the most active congener among the newly synthesized compounds 5a-k with MIC value of 0.0833 µmol/mL as compared with fluconazole (MIC value >1.6325 µmol/mL). Additionally, molecular modeling studies were conducted on a set of anti-Candida albicans compounds. CONCLUSION: The newly synthesized esters 5a-k showed more potent anti-Candida activities than fluconazole. Compounds 7 and 8 revealed significant anti-Candida albicans activity and were able to effectively satisfy the proposed pharmacophore geometry, using the energy accessible conformers (Econf < 20 kcal/mol).

N'-(Adamantan-2-yl-idene)benzo-hydrazide.

The title mol-ecule, C(17)H(20)N(2)O, is a functionalized hydrazine with benzoyl and adamantyl substituents attached to the two hydrazine N atoms. In the crystal, mol-ecules are linked via N-H⋯N hydrogen bonds, forming chains propagating along the a-axis direction. There are also C-H⋯O, C-H⋯N and C-H⋯π inter-actions present within the chains.

(E)-N-[3-(Imidazol-1-yl)-1-phenyl-propyl-idene]hydroxyl-amine.

The title compound, C(12)H(13)N(3)O, exists in an E configuration with respect to the C=N bond [1.285 (2) Å]. The imidazole ring forms a dihedral angle of 75.97 (10)° with the phenyl ring. In the crystal, mol-ecules are linked via O-H⋯N and C-H⋯N hydrogen bonds into sheets lying parallel to (001). The crystal structure also features C-H⋯π inter-actions.

3-(Adamantan-1-yl)-4-(prop-2-en-1-yl)-1H-1,2,4-triazole-5(4H)-thione.

The title mol-ecule, C(15)H(21)N(3)S, exists as the thione tautomer in the solid state. The 1,2,4-triazole ring is almost planar (r.m.s. deviation = 0.004 Å) and the prop-2-en-1-yl chain is close to being perpendicular to this plane [C-N-C-C torsion angle = 77.1 (5)°]. In the crystal, centrosymmetric dimeric aggregates are formed by pairs of N-H⋯S hydrogen bonds as parts of eight-membered (⋯HNCS)(2) synthons. These are connected into layers parallel to (101) via C-H⋯π inter-actions, where the π-system is the triazole ring. The investigated sample was a nonmerohedral twin; the refined domain ratio was 0.655 (4):0.345 (4).