Design, synthesis, biological evaluation and molecular docking of curcumin analogues as antioxidant, cyclooxygenase inhibitory and anti-inflammatory agents

Curcuminoids were isolated from Curcuma longa and their pyrazole and isoxazole analogues were synthesized and evaluated for antioxidant, COX-1/COX-2 inhibitory and anti-inflammatory activities. The designed analogues significantly enhance COX-2/COX-1 selectivity and possess significant anti-inflammatory activity in carrageenan induced rat paw edema assay. Pyrazole, isoxazole analogues of curcumin (4 and 7) exhibited higher antioxidant activity than trolox. Molecular docking study revealed the binding orientations of curcumin analogues in the active sites of COX and thereby helps to design novel potent inhibitors.     

Recent Updates in Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application

Curcumin is an admired, plant‐derived compound that has been extensively investigated for diverse range of biological activities, but the use of this polyphenol is limited due to its instability. Chemical modifications in curcumin are reported to seize this limitation; such efforts are intensively performed to discover molecules with similar but improved stability and better properties. Focal points of these reviews are synthesis of stable pyrazole and isoxazole analogs of curcumin and application in various biological systems. This review aims to emphasize the latest evidence of curcumin pyrazole analogs as a privileged scaffold in medicinal chemistry. Manifold features of curcumin pyrazole analogs will be summarized herein, including the synthesis of novel curcumin pyrazole analogs and the evaluation of their biological properties. This review is expected to be a complete, trustworthy and critical review of the curcumin pyrazole analogs template to the medicinal chemistry community.     

Synthesis and Evaluation of Some Pyrazolo[3,4-d]pyridazinones and Analogues as PDE 5 Inhibitors Potentially Useful as Peripheral Vasodilator Agents

A series of pyrazolo[3,4-d]pyridazinones and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed IC 50 values in the range 0.14-1.4 μM. A good activity and selectivity profile versus PDE6 was found for compound 11e (6-benzyl-3-methyl-1-isopropyl-4-phenylpyrazolo[3,4-d]pyridazin-7(6H)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position-6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five and six membered heterocycles (pyrrole, isoxazole, pyridine and dihydropyridine), as well as some open models were prepared and evaluated. Besides the pyrazole, the best fused systems proved to be isoxazole and pyridine.     

Synthesis and evaluation of some pyrazolo[3,4-d]pyridazinones and analogues as PDE 5 inhibitors potentially useful as peripheral vasodilator agents

A series of pyrazolo[3,4-d]pyridazinones and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed IC50 values in the range 0.14-1.4 microM. A good activity and selectivity profile versus PDE6 was found for compound 11e (6-benzyl-3-methyl-1-isopropyl-4-phenylpyrazolo[3,4-d] pyridazin-7(6H)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position-6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five and six membered heterocycles (pyrrole, isoxazole, pyridine and dihydropyridine), as well as some open models were prepared and evaluated. Besides the pyrazole, the best fused systems proved to be isoxazole and pyridine.     

Binding of isoxazole and pyrazole derivatives of curcumin with the activator binding domain of novel protein kinase C

The protein kinase C (PKC) family of serine/threonine kinases is an attractive drug target because of its involvement in the regulation of various cellular functions, including cell growth, differentiation, metabolism, and apoptosis. The endogenous PKC activator diacylglycerol contains two long carbon chains, which are attached to the glycerol moiety via ester linkage. Natural product curcumin (1), the active constituent of Curcuma L., contains two carbonyl and two hydroxyl groups. It modulates PKC activity and binds to the activator binding site (Majhi et al., Bioorg. Med. Chem.2010, 18, 1591). To investigate the role of the carbonyl and hydroxyl groups of curcumin in PKC binding and to develop curcumin derivatives as effective PKC modulators, we synthesized several isoxazole and pyrazole derivatives of curcumin (2-6), characterized their absorption and fluorescence properties, and studied their interaction with the activator-binding second cysteine-rich C1B subdomain of PKCδ, PKCε and PKCθ. The EC(50)s of the curcumin derivatives for protein fluorescence quenching varied in the range of 3-25 μM. All the derivatives showed higher binding with the PKCθC1B compared with PKCδC1B and PKCεC1B. Fluorescence emission maxima of 2-5 were blue shifted in the presence of the C1B domains, confirming their binding to the protein. Molecular docking revealed that hydroxyl, carbonyl and pyrazole ring of curcumin (1), pyrazole (2), and isoxazole (4) derivatives form hydrogen bonds with the protein residues. The present result shows that isoxazole and pyrazole derivatives bind to the activator binding site of novel PKCs and both carbonyl and hydroxy groups of curcumin play roles in the binding process, depending on the nature of curcumin derivative and the PKC isotype used.     

Perspective: the potential of pyrazole-based compounds in medicine

Pyrazoles are widely used as core motifs for a large number of compounds for various applications such as catalysis, agro-chemicals, building blocks of other compounds and in medicine. The attractiveness of pyrazole and its derivatives is their versatility that allows for synthesis of a series of analogues with different moieties in them, thus affecting the electronics and by extension the properties of the resultant compounds. In medicine pyrazole is found as a pharmacophore in some of the active biological molecules. While pyrazole derivatives have been extensively studied for many applications including anticancer, antimicrobial, anti-inflammatory, antiglycemic, anti-allergy and antiviral, much less has been reported on their metal counterparts in spite of the fact that metals have been shown to impart activity to ligands. Thus this perspective is intended to demonstrate the potential of pyrazole and pyrazolyl metal complexes in the areas of drug discovery and development. Several examples, that include palladium, platinum, copper, gold, zinc, cobalt, nickel, iron, copper, silver and gallium complexes, are used to bolster the above point. For the purposes of this review three areas are discussed, that is pyrazole metal complexes as: (i) anticancer, (ii) antibacterial/parasitic and (iii) antiviral agents.     

Synthesis of pyrazoles and isoxazoles as potent alpha(v)beta3 receptor antagonists

We describe a series of pyrazole and isoxazole analogs as antagonists of the alpha(v)beta3 receptor. Compounds showed low to sub-nanomolar potency against alpha(v)beta3, as well as good selectivity against alpha(IIb)beta3. In HT29 cells, most analogs also demonstrated significant selectivity against alpha(v)beta6. Several compounds showed good pharmacokinetic properties in rats, in addition to anti-angiogenic activity in a mouse corneal micropocket model. Compounds were synthesized in a straightforward manner from readily available glutarate precursors.     

Isoxazole substituted chromans against oxidative stress-induced neuronal damage

We have previously reported that catechol-bearing regioisomers of 5-isoxazolyl-6-hydroxy-chroman display higher in vitro neuroprotective activity, compared to hybrids with other nitrogen heterocycles, but their activity is hampered by cytotoxicity at higher concentrations. In an effort to discover non-cytotoxic isoxazole substituted chromans of high neuroprotective activity, 20 new 3- and 5-substituted (chroman-5-yl)-isoxazoles and (chroman-2-yl)-isoxazoles were synthesized using the copper(I)-catalysed cycloaddition reaction between in situ generated nitrile oxides and terminal acetylenes. An additional aim was to further explore the effect of the isoxazole ring substituents on the neuroprotective activity. The activity of these compounds against oxidative stress-induced death (oxytosis) of neuronal HT22 cells was evaluated and interesting SARs for this group of analogues were derived. The vast majority of new chroman analogues displayed high in vitro neuroprotective activity displaying EC(50) values below 1 μM and lacked cytotoxicity. The position of substituents on the isoxazole ring influences the activity of the regioisomers, with the 3-aryl-5-(chroman-5-yl)-isoxazoles, 17 and 18 and bis-chroman 20 displaying higher neuroprotective activity (EC(50)～0.3 μM) compared to other (chroman-5-yl) and (chroman-2-yl)-isoxazoles.     

Synthesis and anti-neuroinflammatory activity of N-heterocyclic analogs based on natural biphenyl-neolignan honokiol

Novel isoxazole and pyrazole analogs based on natural biphenyl-neolignan honokiol were synthesized and evaluated for their inhibitory activities against nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells. The isoxazole skeleton was constructed via nitrile oxide cycloaddition from oxime 3 and pyrazole was generated by condensation of 4-chromone and alkylhydrazine. Among the analogs, 13b and 14a showed stronger inhibitory activities with IC₅₀ values of 8.9 and 1.2?µM, respectively, than honokiol.     

A combined molecular modeling study on a series of pyrazole/isoxazole based human Hsp90α inhibitors

Inhibition of the protein chaperone Hsp90α is a promising approach for cancer therapy. In this work, a molecular modeling study combining pharmacophore model, molecular docking and three-dimensional quantitative structure-activity relationships (3D-QSAR) was performed to investigate a series of pyrazole/isoxazole scaffold inhibitors of human Hsp90α. The pharmacophore model can provide the essential features required for the biological activities of the inhibitors. The molecular docking study can give insight into the binding mode between Hsp90α and its inhibitors. 3D-QSAR based on CoMFA and CoMSIA models were performed from three different strategies for conformational selection and alignment. The receptor-based models gave the most statistically significant results with cross-validated q ² values of 0.782 and 0.829 and r ² values of 0.909 and 0.968, for CoMFA and CoMSIA respectively. Furthermore, the 3D contour maps superimposed within the binding site of Hsp90α could help to understand the pivotal interaction and the structural requirements for potent Hsp90α inhibitors. The results show 4-position of pyrazole/isoxazole ring requires bulky and hydrophobic groups, and bulky and electron repulsion substituent of 5-amides is favorable for enhancing activity. This study will be helpful for the rational design of new potent Hsp90α inhibitors.     

Fluorinated acyclo-C-nucleoside analogues from glycals in two steps

A convenient two-step strategy is reported for the synthesis of fluorinated optically pure acyclo-C-nucleoside analogues starting from simple glycals. In the first step, benzyl- or p-methoxybenzyl-protected glycals are treated with trifluoroacetic anhydride, bromodifluoroacetyl chloride, trichloroacetyl chloride, and perfluorooctanoyl chloride, respectively, in the presence of Et3N. This one-pot procedure yields 1,2-unsaturated sugars (1,5-anhydro-3,4,6-tri-O-benzyl (or p-methoxybenzyl) 2-deoxy-2-perhalogenoacyl-D-arabino / lyxo-hex-1-enitols 4-9) acylated at C-2. In the second step, a selective ring transformation is induced by treatment of the C-acylated glycals with bis-nucleophiles (hydrazine, phenylhydrazine, o-phenylenediamine, hydroxylamine). In particular, 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-trifluoroacetyl-D-arabino-hex-1-enitol (4) and 1,5-anhydro-2-deoxy-2-trifluoroacetyl-3,4,6-tri-O-(p-methoxybenzyl)-D-arabino-hex-1-enitol (8) were reacted with these nucleophiles generating the final C-nucleoside analogues of pyrazole (10, 11, and 12), diazepine (13), and isoxazole (15), respectively, containing a carbohydrate side chain linked to the heterocyclic ring.     

Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains

Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.     

Interaction of dopamine beta-mono-oxygenase with substituted imidazoles and pyrazoles. Catalysis and inhibition.

The interaction of dopamine beta-mono-oxygenase (DBM) with substrate analogues possessing either imidazole or pyrazole functionalities at the alkyl chain terminus was investigated. 1-(4-Hydroxybenzyl)imidazole (4-HOBI) is an active substrate for DBM, and it exhibits the expected ascorbate- and fumarate-dependencies and normal kinetic behaviour at concentrations up to 10 mM. 4-Hydroxybenzaldehyde was identified as the product formed from 4-HOBI on the basis of h.p.l.c. and g.c.-m.s. analysis, and its formation exhibits the expected 1:1 stoichiometry with O2 consumption. The 4-HOBI/DBM reaction is kinetically comparable with other DBM activities, and 4-HOBI is the first substrate analogue yet reported that exhibits substantial activity though lacking a terminal amino group. Introduction of a methyl substituent at the 2-position of the imidazole ring abolishes substrate activity, probably through a steric effect. 1-(4-Hydroxybenzyl)pyrazole, where imidazole is replaced by the isomeric pyrazole moiety, is a potent DBM inhibitor, and not a substrate. These results represent the first report of an active heterocyclic substrate or inhibitor for this enzyme, and establish the basis for the design of new classes of DBM substrates and inhibitors.     

Comparative studies on the mechanism of cytotoxic action of novel platinum II complexes with pyrazole ligands

In search for new platinum-based anticancer drugs, four cisplatin analogues, which contain pyrazole rings as non-leaving ligands, have been synthesized: cis-PtCl(2)(3,5-DM HMPz)(2), cis-PtCl(2)(Pz)(2), cis-PtCl(2)(ClMPz)(2), and cis-PtCl(2)(HMPz)(2), where Pz=pyrazole, H=hydroxyl, M=methyl. We tested their cytotoxicity, apoptosis induction ability, DNA damaging and modification properties comparing them in respect to the parent compound. The cytotoxic activity of these platinum pyrazole complexes toward the murine leukemia cell line was 2.9-3.8 times lower than actvity of cisplatin. The tested compounds varied in their mechanism of action by producing different DNA lesions. The most interesting compound seems to be the complex with chloromethyl groups at N1 of pyrazole rings, which exhibited the highest ability to form bifunctional adducts with DNA in vitro.     

Antimycobacterial activity: synthesis of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues

In this study, a series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized and evaluated for antimycobacterial activity against Mycobacterium tuberculosis (MTB) H(37)Rv and isoniazid resistant M. tuberculosis (INHR-MTB). All the newly synthesized compounds were showing moderate to high inhibitory activities. The compound 6,7-dimethoxy-3-(4-chloro phenyl)-4H-indeno[1,2-c]isoxazole (4b) was found to be the most promising compound, active against MTB H(37)Rv and INHR-MTB with minimum inhibitory concentrations of 0.22 and 0.34 μM.     

Synthesis of some novel androstanes as potential aromatase inhibitors

Novel pyrazole and isoxazole derivatives (6-9) were synthesized as a aromatase inhibitors. Pyrazole was synthesized from hydrazine hydrate and isoxazoles from hydroxylamine hydrochloride under different conditions. Molecular docking studies were carried out for the synthesized compounds. The best score was obtained for the compound (9) followed by compound (6) while compound (8) afforded poorest of the score. Aromatase inhibitory activity for compound (6) having pyrazole ring at 2,3 position showed highest activity followed by nitrile derivative (9). Isomeric forms of isoxazole (7 and 8) showed very poor activity compared to fadrozole and aminoglutethimide. Preliminary kinetic studies have shown that both of the active compounds (6 and 9) are reversible inhibitors of the enzyme.     

Carbon–carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon–carbon linked pyrazolylphenyl analogues has been prepared. The -N-substituted methyl pyrazole (10) in the C3-linked series exhibited very good Gram-positive activity with MICs ≤0.5–1 μg/mL and moderate Gram-negative activity with MICs=2–8 μg/mL against Haemophilus influenzae and Moraxella catarrhalis. This analogue was also found to have potent in vivo activity with an ED₅₀=1.9 mg/kg. β-Substitution at the C3-linked pyrazole generally results in a loss of activity. The C4-linked pyrazoles are slightly more potent than their counterparts in the C3-linked series. Most of the analogues in the C4-linked series exhibited similar levels of activity in vitro, but lower levels of activity in vivo than 10. In addition, incorporation of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to compounds several times more potent than eperezolid, linezolid and vancomycin. The thioamide of the N-cyanomethyl pyrazole analogue (34) exhibited an exceptional in vitro activity with MICs of ≤ 0.06–0.25 μg/mL against Gram-positive pathogens and with MICs of 1 μg/mL against fastidious Gram-negative pathogens.     

Pyrazole-O-glucosides as novel Na(+)-glucose cotransporter (SGLT) inhibitors

O-glucuronides and O-glucosides of a series of pyrazoles analogues were synthesized and evaluated for their SGLT inhibitory activity in brush border membrane vehicles (BBMVs) of rat kidney. O-glucosides of certain pyrazole analogues inhibited the transport of [(14)C]-glucose in BBMVs, and induced glucosuria in Wistar rats by intravenous injection.     

Synthesis and tubulin-binding properties of non-symmetrical click C5-curcuminoids

A click-type entry into shortened curcuminoids of the diarylpentanoid type has been developed. The reaction is ideally suited to generate non-symmetrical analogues of curcumin, a class of natural products difficult to access but of growing biomedical relevance and special mechanistic interest to investigate the unique binding mode of curcumin to tubulin. Investigation of a series of click diarylpentane curcuminoids and their pyrazole adducts in various cellular tubulin functional assays validated this class of compounds as a novel type of anti-mitotic agents, evidencing structure–activity relationships, and identifying the pyrazole adduct 4k as a promising lead.     

Isoxazole-type derivatives related to combretastatin A-4, synthesis and biological evaluation

Novel combretastatin analogues bearing various five-membered heterocycles with consecutive oxygen and nitrogen atoms, in place of the olefinic bridge of CA4, have been synthesized (isoxazole, isoxazoline, oxadiazole, etc). These compounds have been evaluated for cytotoxicity and their ability to inhibit the tubulin assembly. On the basis of the relative position of the aromatic A- and B-rings on the heterocyclic moiety, they could be split in two classes, the alpha,gamma- or alpha,beta-diaryl heterocyclic derivatives. In the first series, the 3,5-diaryloxadiazole 9a displayed comparable antitubulin activity to that of CA4, but was devoid of cytotoxic effects. Among the alpha,beta-diaryl heterocyclic derivatives, the 4,5-diarylisoxazole 35 exhibited greater antitubulin activity than that of CA4 (0.75 vs 1.2 microM), but modest antiproliferative activity. These data showed that minor alteration in the chemical structure of the heterocyclic ring and its relative orientation with regard to the two phenyl rings of CA4 could dramatically influence the tubulin binding properties.