An Exhaustive Compilation on the Synthesis of Heterocycles Pendant on the Fatty Acid Alkyl Chains.

Fatty acids derived from oils and fats of different plant and animal resources are considered one of the most valuable renewable precursors of the synthetic chemical and pharmaceutical industries. On the other hand, heterocyclic compounds are well known nowadays by their constitution of many commercialized drugs due to their unique biological activities. Combination between fatty acids and heterocyclic compounds has made important advances in the construction of valuable biologically relevant molecules in pharmaceutical industry. This review casts light on the synthetic pathways for construction of the fatty acid-heterocycle hybrid up to date in a simple classification and arranged manner.

Novel thiazole derivatives incorporating phenyl sulphonyl moiety as potent BRAFV600E kinase inhibitors targeting melanoma.

Novel thiazole derivatives possessing phenyl sulfonyl moiety were designed and synthesized as B-RAFV600E kinase inhibitors based on the clinically-approved anticancer drug, dabrafenib. All target compounds showed significant inhibition of B-RAFV600E kinase enzyme at nanomolar levels. Compounds 7b and 13a revealed excellent B-RAFV600E inhibitory activity, superior to that of dabrafenib with IC50 values of 36.3 ± 1.9, 23.1 ± 1.2, and 47.2 ± 2.5 nM, respectively. Moreover, the title compounds were much more selective toward B-RAFV600E kinase than B-RAF wild type. In addition, the most potent compounds were further evaluated for their anticancer activity against B-RAFV600E-mutated and wild type melanoma cells. A positive correlation between the cytotoxic activity and selectivity for B-RAF V600E over B-RAF wild type was clearly observed for compounds 7b, 11c, 13a, and 17. All the screened compounds potently inhibited the growth of WM266.4 melanoma cells with IC50 values in the range from 1.24 to 17.1 µM relative to dabrafenib (IC50 = 16.5 ± 0.91 µM). Compounds 7b, 11a and 11c, 13a, and 17 were much more potent than dabrafenib against B-RAFV600E-mutated WM266.4 melanoma cells. Furthermore, compound 7b suppressed the phosphorylation of downstream ERK1/2 from WM266.4 cells. Also, the docking study revealed the proper orientation and well-fitting of the title compounds into the ATP binding site of B-RAFV600E kinase.

Design, synthesis, cytotoxicity, and molecular docking studies of novel thiazolyl-hydrazone derivatives as histone lysine acetyl-transferase inhibitors and apoptosis inducers.

Compounds containing both thiazole and arylsulfone moieties are recognized for their high biological activity and ability to fight a variety of ailments. Thus, in this context, new derivatives of (thiazol-2-yl)hydrazone with an arylsulfone moiety were synthesized as CPTH2 analogs with potent anti-histone lysine acetyl-transferase activity. Compounds 3, 4, 10b, and 11b showed an excellent inhibitory effect on P300 (E1A-associated protein p300), compared to CPTH2. Among all the tested derivatives, compound 10b revealed the highest activity against both P300 and pCAF. In addition, the new hits were tested for anticancer efficacy against two leukemia cell lines. Most of them showed a moderate to potent antitumor effect on the k562 and CCRF-CEM cell lines. Interestingly, the activity of compound 10b against the k562 cell line was found to be higher than that of CPTH2. Furthermore, it showed a good safety profile, better than CPTH2 on normal cells. Molecular docking analysis was carried out to reveal the crucial binding contacts in the inhibition of the P300 and pCAF enzymes.

Novel sulfonyl thiazolyl-hydrazone derivatives as EGFR inhibitors: Design, synthesis, biological evaluation and molecular docking studies.

New hydrazonoyl-sulfonylthiazoles were designed and synthesized as EGFR inhibitors. The new sulfonylthiazole derivatives were assessed in vitro to measure their effect on EGFR. They revealed marked inhibitory activity against EGFR kinase having IC50 range from 0.037 to 0.317 µM compared to reference drug dasatinib (IC50 = 0.077 µM). Six derivatives of the newly synthesized compounds showed potent inhibitory activity relative to dasatinib. Furthermore, the new hits were examined concerning their cytotoxic effect on human breast cancer cell line (MCF7), hepatic cancer cell line (HepG2) using MTT assay. N-(2-Benzenesulfonyl-1-phenyl-ethylidene)-N'-(4-methyl-thiazol-2-yl)-hydrazine (IC50 = 1.24 µM) revealed higher potency than dasatinib (IC50 = 11.6 µM) against MCF7cell line. Besides, N-(2-benzenesulfonyl-1-phenyl-ethylidene)-N'-(4-methyl-5-p-tolylazo-thiazol-2-yl)-hydrazine exhibited excellent cytotoxicity against HepG2cell line (IC50 = 3.61 µM), exceeding that of dasatinib (IC50 = 14.10 µM). In addition to low cytotoxic effect on normal (WI-38) cells, describing the high safety profiles of these compounds. Moreover, molecular docking was done in order to determine the possible binding modes of such compounds inside the binding site of EGFR.

Recent Advances in Synthesis and Reactions of ß-Amino-α ,ß -Enones (Enaminones).

ß-Amino-α,ß-enones or ß-enamino carbonyl compounds are versatile synthons intermediates for the construction of various bio-active heterocyclic compounds and have been established as multipurpose synthetic precursors in organic syntheses and in pharmaceutical developments. In this work, we will discuss the different synthetic routes to obtain ß-amino-α,ß-enones or ß-enamino carbonyl compounds, their reactions, and their utility in the construction of organic frameworks and heterocyclic ring systems. Structurally, ß- amino-α,ß-enones are attractive intermediates that syndicate the ambident behaviours of nucleophilicity and electrophilicity of enones at the same time. ß-amino-α,ß-enones have been known as acceptors in both 1,2- and 1,4- additions that make them good intermediate compounds for annulation to different heterocycles.

Synthesis of Thiazolyl-N-phenylmorpholine Derivatives and their Biological Activities.

BACKGROUND: Morpholine and thiazole rings are two heterocycles which are wellknown with a wide spectrum of different biological activities, especially antitumor activity. OBJECTIVE: The aim of the work is to design and synthesize hybrid heterocyclic compounds of morpholine and thiazole moieties via the reaction of morpholino-thiosemicarbazone derivatives with various α-halocarbonyl compounds and screening their antitumor activity against three tumor cell lines namely, TK-10, MCF-7 and UACC-62. METHODS: An efficient synthesis of a series of N-phenylmorpholine derivatives linked with thiazole moiety was accomplished. The reaction of N-subistituted-2-(N-phenylmorpholine)ethylidene) hydrazine- 1-carbothioamide (thiosemicarbazone derivative) with acetyl and ester-hydrazonoyl chlorides, α-chloroketones, or α-bromoesters afforded the corresponding thiazole derivatives pendent to N-phenylmorpholine moiety in good to excellent yields. RESULTS: Mass, 1H NMR, 13C NMR, and elemental analysis were used to confirm the structure of all the new derivatives. The antitumor activities of synthesized N-phenylmorpholine-thiazole derivatives were investigated against three tumor cells namely, TK-10, MCF-7 and UACC-62. The results of such investigation indicated that some derivatives showed good potential to inhibit the growth of the two cells of the tested tumor cells. One of the tested compounds, N-ethyl thiosemicarbazone derivative 7 revealed potent growth inhibition of all the three tumor cells. CONCLUSION: We have succeeded to synthesize a series of N-phenylmorpholine derivatives pendant to thiazole moiety as antitumor agents.

Cytotoxicity, Docking Study of New Fluorinated Fused Pyrimidine Scaffold: Thermal and Microwave Irradiation Synthesis.

BACKGROUND: Azolopyrimidines are imposed on the arena of drugs treated for cancer. The urgent need to discover new selective anticancer agents, paved the way to explore the antitumor significance of such fused systems. From the synthetic point of view, Microwave facilitated technique for synthesis is very strongly associated with green method in chemistry field. AIM: Our aim is to synthesize bioactive compounds using docking simulation run by MOE program to explore the binding mode of the most active enzyme inhibitor among the target compounds. METHODS: In addition to the use of conventional heating, the MARS system of CEM utilized for Microwave irradiation that is equipped with a multi-mode platform with a magnetic stirring plate and a rotor that allows the parallel processing of many vessels per batch. All the synthesized compounds were tested for their anticancer activity against hepatic cancer (HepG-2), breast cancer (MCF-7) and colon cancer (HCT-116). Screening against the cancer cell lines was performed, using doxorubicin as a reference drug. Docking studies were conducted using MOE software. RESULTS: A novel series of fluorinated fused-pyrimidine namely, pyrazolopyrimidine, triazolopyrimidine and pyrimidobenzimidazole were designed and synthesized conventionally and under microwave irradiations. The mechanistic pathways as well as the structure of all products were debated and demonstrated based on all possible spectral data. In-vitro examination of the novel prepared derivatives versus the three different human cancer cell lines [hepatic cancer (HepG-2), breast cancer (MCF-7) and colon cancer (HCT-116)] was evaluated to estimate their actual activity. CONCLUSION: We have developed a simple, facile, and efficient procedure for the formation of new series of azolopyrimidines. All spectra of all products were investigated deliberately to confirm their structures. The anti-cancer activity has been examined against three cancer cell lines e.g. HepG-2, MCF-7 and HCT116. Molecular modeling study was carried out in order to rationalize the in vitro anti-tumor results.

Novel 2-indolinone thiazole hybrids as sunitinib analogues: Design, synthesis, and potent VEGFR-2 inhibition with potential anti-renal cancer activity.

Novel 2-indolinone thiazole hybrids were designed and synthesized as VEGFR-2 inhibitors based on sunitinib, an FDA-approved anticancer drug. The proposed structures of the prepared 2-indolinone thiazole hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-VEGFR-2 activity. All tested compounds exhibited a potent submicromolar inhibition of VEGFR-2 kinase with IC50 values ranging from 0.067 to 0.422 µM, relative to sunitinib reference drug (IC50 = 0.075 ± 0.002 µM). Compounds 5, 15a, 15b, 17, 19c displayed excellent VEGFR-2 inhibitory activity, comparable or nearly equipotent to sunitinib. Compound 13b stood out as the most potent against VEGFR-2 showing IC50 value of 0.067 ± 0.002 µM, lower than that of sunitinib. In addition, the most potent derivatives were assessed for their anticancer activity against two renal cancer cell lines. Compound 13b (IC50 = 3.9 ± 0.13 µM) was more potent than sunitinib (IC50 = 4.93 ± 0.16 µM) against CAKI-1 cell line. Moreover, thiazole 15b displayed excellent anticancer activity against CAKI-1 cell line (IC50 = 3.31 ± 0.11 µM), superior to that of sunitinib (IC50 = 4.93 ± 0.16 µM). Thiazole 15b was also equipotent to sunitinib (IC50 = 1.23 ± 0.04 µM) against A498 cell line. Besides, compound 15b revealed a safety profile much better than that of sunitinib against normal human renal cells. Furthermore, a docking study revealed a proper fitting of the most active compounds into the ATP binding site of VEGFR-2, rationalizing their potent anti-VEGFR-2 activity.

Synthesis and DNA binding of novel bioactive thiazole derivatives pendent to N-phenylmorpholine moiety.

An easy access to a series of N-phenylmorpholine derivatives linked with thiazole or formazan moieties were achieved using simple experimental procedure under conventional and microwaves irradiation conditions. The reaction of 2-(N-phenylmorpholine)ethylidene)hydrazine-1-carbothioamide derivatives and [1-(4-morpholin-4-yl-phenyl)-ethylidene]-hydrazine with a variety of hydrazonoyl chlorides or phenacyl bromide derivatives afforded the corresponding thiazoles or N-substitutedhydrazino-derivatives linked to N-phenylmorpholine moiety in good to excellent yields. The structures of the newly synthesized compounds were fully emphasized and characterized by spectroscopic as well as elemental analyses. The mode of binding of some selected compounds with SS-DNA was evaluated using UV-Vis absorption, and viscosity measurements. The results showed intercalation binding mode of most of the tested compounds. Both antimicrobial and anti-cancer activities have been studied for some selected compounds from synthetic derivatives. Their results showed a remarkable efficacy for some derivatives against both examined microbes and cancer cells.

Synthesis and Antimicrobial Evaluation of Novel Pyrazolopyrimidines Incorporated with Mono- and Diphenylsulfonyl Groups.

A novel series of pyrazolo[1,5-a]pyrimidine ring systems containing phenylsulfonyl moiety have been synthesized via the reaction of 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl) phenyl)ethan-1-one, 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-3-dimethylamino-propenone and 3-(dimethylamino)-1-(4-(phenylsulfonyl)phenyl)prop-2-en-1-one each with various substituted aminoazopyrazole derivatives in one pot reaction strategy. The proposed structure as well as the mechanism of their reactions were discussed and proved with all possible spectral data. The results of antimicrobial activities of the new sulfone derivatives revealed that several derivatives showed activity exceeding the activity of reference drug. Contrary to expectations, we found that derivatives containing one sulfone group are more effective against all bacteria and fungi used than those contain two sulfone groups.

Pyrimidyl formamidine palladium(II) complex as a nanocatalyst for aqueous Suzuki-Miyaura coupling.

Synthesis of a new phosphene-free nano-size formamidine-based palladium complex have been achieved. The molecular structure of novel palladium complex have been confirmed using spectroscopic methods of analysis as well as physical characterizations. The synthesized complex has been used as a catalyst for microwave assisted aqueous Suzuki-Miyaura Cross-coupling (SMC) of aryl bromides with phenylboronic acid. The formamidine-based Pd(II)-complex exhibited excellent catalytic activity to obtain biaryls using mild reaction conditions.

An overview on synthetic strategies for the construction of star-shaped molecules.

Strategies for the synthesis of star-shaped molecules have been in high demand in the last decades due to the importance of those compounds in various fields. The distinctly different properties of these compounds compared to their linear analogues make them versatile building blocks for the formation of mesophases of interesting mesomorphic and photophysical properties. Moreover, the applications of star-shaped molecules as building units for dendrimers as well as in supramolecular host-guest chemistry have also been recently studied. The star-shaped molecules mentioned in this review are classified according to the central core as well as the type of side arms. The properties and applications of these compounds are described in the appropriate contexts. This report summarizes the recent advances in this area.

Indomethacin Analogs: Synthesis, Anti-inflammatory and Analgesic Activities of Indoline Derivatives.

BACKGROUND: Microwave assisted reactions offer a considerable advantages over conventional method reactions because the former results in substantial rate enhancement in a wide range of organic reactions. OBJECTIVE: we interested herein to prepare new anti-inflammatory and analgesic agents analogues to Indomethacin in short reaction time by using microwaves irradiation. METHOD: Synthesis of new hydrazonoindolines having thiazole moiety under microwave irradiation were achieved via the reaction of hydrazonoyl chlorides or halogenated active methylene derivatives with thiosemicarbazone derivatives. Also, the utility of the versatile indoline-2,3-dione derivatives in the design of new multifunctional building blocks using condensation with hydrazine derivatives was demonstrated. RESULTS: All products were formed in short reaction time and high yield. The information derived from the spectral data of the formed compounds was confirmed their structures. Also, the analgesic and antiinflammatory activities of the designed derivatives were screened and the results obtained indicated that six derivatives 4g, 9b, 4c, 10b, 4d and 11a revealed the highest anti-inflammatory and analgesic effects. CONCLUSION: we succeeded in this context to design and synthesis of new anti-inflammatory and analgesic agents analogues to Indomethacin in short reaction time and with high yield.

Novel pyridine-based Pd(II)-complex for efficient Suzuki coupling of aryl halides under microwaves irradiation in water.

Suzuki C-C cross-coupling of aryl halides with aryl boronic acids using new phosphene-free palladium complexes as precatalysts was investigated. A pyridine-based Pd(II)-complex was used in open air under thermal as well as microwave irradiation conditions using water as an eco-friendly green solvent.

New formamidine ligands and their mixed ligand palladium(II) oxalate complexes: Synthesis, characterization, DFT calculations and in vitro cytotoxicity.

A series of new ternary palladium(II) complexes of the type [Pd(L1-4)ox]·xH2O where L=formamidine ligands and ox=oxalate, were synthesized and characterized by elemental analyses, magnetic susceptibility, UV-Vis, infrared (IR) and mass spectroscopy and thermal analysis. The spectroscopic data indicated that the formamidine ligands act as bidentate N2 donors and the oxalate as O2 ligand. The complexes (1-4) are diamagnetic and the optimization of their structures indicated that the geometry is distorted square planer with O-Pd-O and N-Pd-N bond angles ranged 82.70-83.87° and 88.21-95.02°; respectively which is acceptable for the heteroleptic complexes. The dipole moment of the complexes (13.97-18.77Debye) indicating that the complexes are more polarized than the ligands (1.93-4.96Debye). The complexes are thermally stable as shown from their relatively higher overall activation energies (441-688kJmol(-1)). The ligands and the complexes are proved to have good cytotoxicity with IC50 (µM) in the range of (0.011-0.168) against MCF-7, (0.012-0.150) against HCT-116, (0.042-0.094) against PC-3 and (0.006-0.222) against HepG-2 cell lines, which open the field for further application as antitumor compounds.

Synthesis, Spectral Characteristics and DFT Studies of the New Dye 2,7-diacetyl-9-((dimethylamino)methylene)-9H-fluorene (DMMF) in Different Solvents.

The photophysical parameters such as electronic absorption spectra, molar absorptivity(ε), fluorescence spectra and fluorescence quantum yield (φf) of a new dye namely 2,7-diacetyl-9-((dimethylamino)methylene)-9H-fluorene (DMMF) were determined in different solvents. The electronic absorption are less sensitive to medium polarity. A bathochromic shift was observed in emission spectra(ca. 50 nm) upon increase of solvent polarity, which indicates that the singlet excited state (S1) of DMMF is more polar than the singlet ground state (So). Solid crystals of DMMF exhibit intense yellow fluorescence maximum at 550 nm with bandwidth equal 64 nm upon excitation at wavelength 365 nm. The change in dipole moment value (Δµ) was calculated by using the variation of Stokes shift with solvent polarizability (Δf) (Lippert - Mataga plot) and was found to be 7.22 and 5.5 Debye for higher and lower energy of So - S1 (π-π*) H-1 → L and So - S1 (π-π*) H → L, respectively. These results show that, the excited state is more polar than the ground state. The net photochemical quantum yields of photodecomposition of DMMF (φc) were calculated as 7.2 × 10(-5), 1.14 × 10(-4), 1.44 × 10(-4) and 2.11 × 10(-4) in different solvents such as MeOH, CH2Cl2, CHCl3 and CCl4, respectively. DFT/TD-DFT methods were used to study the geometric and electronic structures of DMMF in different solvents. A good agreement was found between the experimental and theoretical results.

Regioselective synthesis and ab initio calculations of fused heterocycles thermally and under microwave irradiation.

Pyrazolo[1,5-a]pyrimidine, triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazole, pyrido[1,2-a]benzimidazole ring systems incorporating phenylsulfonyl moiety were synthesized via the reaction of 3-(N,N-dimethylamino)-1-(thiophen-2-yl)-2-(phenylsulfonyl)prop-2-en-1-one derivatives with the appropriate aminoazoles as 1,3-binucleophiles and 1H-benzimidazol-2-ylacetonitrile using conventional methods as well as microwave irradiation. The regioselectivity of the cyclocondensation reactions was confirmed both experimentally by alternative synthesis of reaction products and theoretically using ab initio quantum chemical calculations namely the Density Functional Theory (DFT). The theoretical work was carried out using the Becke, three parameter, Lee-Yang-Parr hybrid functional (B3LYP) combined with the 6-311++G(d,p) basis set. It was found that the final cyclocondensation reaction product depends mainly on the initial addition to the activated double bond by the nitrogen atom of the 1,3-binucleophiles that has the higher electron density.

Microwave assisted synthesis of bis and tris(ω-bromoacetophenones): versatile precursors for novel bis(imidazo[1,2-a]pyridines), bis(imidazo[1,2-a]pyrimidines) and their tris-analogs.

BACKGROUND: α-Bromination of the side chain of aromatic ketones using NBS in the presence of p-toluenesulfonic acid (p-TsOH) in acetonitrile is very common. However, regioselective bromination of bis and tris(ω-bromoacetophenones) with NBS in the presence of p-TsOH in acetonitrile under microwave irradiation is quite novel. The bis- and tris(ω-bromoacetophenones) are used in synthesis of bis and tris(heterocycles). bis(heterocycles) have received a great deal of attention, because many biologically active natural and synthetic products have molecular symmetry. The use of the pressurized microwave irradiation is very advantageous to many syntheses and provide a large rate enhancement. RESULTS: Bis and tris(ω-bromoacetophenones) were obtained as single monobrominated derivatives in a shorter time than the conventional conditions. The results clearly demonstrate the better reactivity and selectivity of NBS/p-TsOH/CH3CN as a brominating mixture under microwave conditions. The reaction of bis and tris(ω-bromoacetophenone) with 2-aminopyridine and 2-aminopyrimidine proceeded smoothly in a mixture of anhydrous ethanol and DMF under reflux or using 300 W/105°C/ 20 min microwave irradiation conditions to afford the corresponding bis(imidazo[1,2-a]pyridine), bis(imidazo[1,2-a]pyrimidine) and tris(imidazo[1,2-a]pyridine) derivatives in moderate to excellent yields. The carbonyl analogue of the targeted bis(imidazopyridines) could be synthesized by the reaction of N,N-dimethyl-N'-(pyridin-2-yl)formimidamide with bis(ω-bromoacetophenone) in refluxing ethanol. The structures of the newly synthesized compounds were confirmed by their spectral data as well as their elemental analyses. CONCLUSION: In conclusion, selective α-bromination of bis- and tris(acetophenones) has been accomplished efficiently utilizing NBS/p-TsOH/CH3CN under microwave irradiation. In addition, a facile synthesis of novel series of bis- and tris(imidazopyridine) and bis(imidazopyrimidine) derivatives.

Recent advances in the therapeutic applications of pyrazolines.

INTRODUCTION: Pyrazolines are well-known and important nitrogen-containing five-membered ring heterocyclic compounds. Various methods have been worked out for their synthesis. Several pyrazoline derivatives have been found to possess diverse biological properties, which has stimulated research activity in this field. AREAS COVERED: The present review sheds light on the recent therapeutic patent literature (2000 - 2011) describing the applications of pyrazolines and their derivatives on selected activities. Many of the therapeutic applications of pyrazoline derivatives have been discussed, either in the patent or in the general literature areas in this review. In addition to selected biological data, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized. EXPERT OPINION: Pyrazoline derivatives have numerous prominent pharmacological effects, such as antimicrobial (antibacterial, antifungal, antiamoebic, antimycobacterial), anti-inflammatory, analgesic, antidepressant and anticancer. Further pharmacological effects include cannabinoid CB1 receptor antagonists, antiepileptic, antitrypanosomal, antiviral activity, MAO-inhibitory, antinociceptive activity, insecticidal, hypotensive, nitric oxide synthase inhibitor, antioxidant, steroidal and antidiabetic. Lastly, they also effect ACAT inhibition, urotensin II and somatostatin-5 receptors, TGF-ß signal transduction inhibitors and neurocytotoxicity inhibitors activities. Many new pyrazoline derivatives have been synthesized and patented, but there are still new aspects to explore and work on.

Single step synthesis of new fused pyrimidine derivatives and their evaluation as potent Aurora-A kinase inhibitors.

A simple, facile, efficient and one pot three-component procedure for the synthesis of pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and pyrimido[1,2-a]benzimidazoles ring systems incorporating phenylsulfonyl moiety was developed via the reaction of 1-aryl-2-(phenylsulfonyl)ethanone derivatives 1a-d with the appropriate heterocyclic amine and triethyl orthoformate and evaluated as Aurora-A kinase inhibitors. The cytotoxic activity of the newly synthesized compounds against HST116 colon tumor cell line was investigated. 2,7-Diphenyl-6-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidine (4b) and its p-methoxy analogue 4c were found to be equipotent to Doxorubicin as a reference drug. Molecular modeling study was carried out in order to rationalize the in vitro anti-tumor results.