Medicinal Chemistry - Volume 9, Issue 4, 2013

Series of structurally varied N-alkyl 1,4-dihydropyridines and novel benzo-annelated derivatives as 1,4- dihydroquinolines have been characterized as ABCB1 inhibitors. Structure-activity relationships (SARs) are discussed. Cytotoxic activities of selected compounds have been determined. A first bioanalysis of ABCB1 substrate properties has been carried out in a cell-based model. Compounds with highest ABCB1 inhibiting activities were no substrates of ABCB1 and not transported by the efflux pump, thus profiling the new ABCB1 inhibitors.

The Ko family of fumitremorgin C analogs are potent and selective ABCG2 inhibitors. However, the most potent Ko compounds carry an ester linkage in their side-chain that makes them chemically and metabolically less stable. We have synthesized 16 tricyclic and 28 tetracyclic novel analogs devoid of ester linkages and tested them for ABCG2 inhibition potency and specificity. Unlike in the tricyclic analog group, potent ABCG2 inhibitory compounds were found among the tetracyclic analogs. The most potent compounds carried the 3S,6S,12aS configuration. We observed a marked stereospecificity as compounds with the 3S,6S,12aS configuration were at least 18-fold more potent inhibitors than their diastereoisomeric pairs with a 3S,6R,12aS configuration. This stereospecificity was not observed in ABCB1 and ABCC1 inhibition. Therefore, a single chiral center confers specificity for ABCG2 over ABCB1 and ABCC1. This is quite unexpected considering the large multivalent drug binding site these transporters harbor.

It has been shown that some chalcones are able to inhibit tubulin polymerization, giving cytotoxicity and destruction of tumoral vasculature. A library of 180 novel chalcone analogs has been synthesized via click chemistry and screened for their cytotoxicity and tubulin assembly inhibition. 10 out 180 click chalcones displayed low micromolar cytotoxicity but only compound Nf depicted antitubulin activity. While Nf displayed only micromolar potency this result shows click-chalcones may be anti-tubulin agents and validate this strategy to search for novel active chemical entities.

Relationship between activity and structure of the selected 4-chloro-2-mercapto-5-methylbenzensulfonamide derivatives with their potential anticancer activity was studied. Lipophilicity was determined using two distinct chromatographic methods. Moreover, geometry of studied compounds was optimized with the help of HyperChem software to obtain some molecular descriptors. Reversed-phase and micellar liquid chromatography lipophilicity parameters together with theoretically calculated parameters were used to study the relationship between structure and activity. Principal component analysis performed firstly on activity data and secondly on molecular parameters revealed similar results, which allowed us to divide studied set of compounds into three distinct clusters differing in both structure and activity. Moreover, stepwise regression analysis led to statistically significant equation describing potential anticancer activity of studied derivatives based on nuclear energy and log P (partition coefficient) of compounds.

Tumor and especially breast cancer is among the most common causes of death worldwide. Finding novel nanosized therapeutic compounds have important role to decrease the chance of death and increase the survival. Cancer cells are highly attractive to glucose [with a nanosize bimolecular structure 1nm] as an energy source more than normal cell and nanosized therapeutics due to possessing different pharmacokinetic and pharmacodynamic have advantageous over classical dosage forms in cancer therapy. The aim of the study was to synthesize Glucosamin-Porphyrin-Tamoxifen [TPG] nanosized complex as a novel selective biocompatible anti breast cancer agent. After the synthesis procedure, this complex was purified and then tested In Vitro on breast cancer cells [MCF-7] in the absence or presence of the red light and found totally successful. The results showed a good anti breast cancer activity mediated by the activation of TNF-α and necrosis/apoptosis pathways for the nanosized complex with no alteration effects on blood PT/APTT and glucose or hexokinase levels/ activity. TPG nanoconjugate seems to be very good opponents to current anti breast cancer drugs and needs to be further investigated in near future.

As a part of our continued studies on trans-planaramineplatinum(II) complexes, we report here the synthesis and in vitro activity in the human ovarian tumour models of trans-(4-hydroxypyridine)(ammine)dichloroplatinum(II)] (coded as DH1). Although less active than cisplatin against the parent ovarian A2780 and the resistant A2780^cisR and A2780^ZD0473R cell lines, it has much lower resistant factors than cisplatin. The results indicate that at the level of its activity, DH1 has been better able to overcome the mechanisms of resistance operating in the A2780^cisR and A2780^ZD0473R cell lines. When platinum–DNA binding levels at 24 h in the A2780, A2780^cisR and A2780^ZD0473R cell lines are compared it is found that DH1 has higher levels of platinum binding with the DNA than cisplatin even though it has lower activity than cisplatin. The lack of correlation between activity and the platinum–DNA binding level as applied to cisplatin and DH1 may not be so unexpected when we note that the two compounds will differ in their nature of interaction with the DNA. Whereas cisplatin binds with DNA forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH1 is expected to form more of 1,2-interstrand Pt(GG) and monofunctional Pt(G) and Pt(A) adducts, thus bringing about different conformational changes in the DNA. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion showed that DH1 was less able to prevent BamH1 digestion than cisplatin, indicating that cisplatin caused a greater conformational change in the DNA than DH1. Lower activity of DH1 as compared to analogous trans-platinums containing ligands such as 3-hydroxypyridine, 2-hydroxypyridine and imidazo(1,2-α-pyridine) can be seen to illustrate structureactivity relationships. In particular, it supports the idea that, in trans-planaramineplatinum(II) complexes, the ligands 2- hydroxypyridine, 3-hydroxypyridine and imidazo(1,2-α-pyridine) are much more activating towards antitumour activity than 4-hydroxypyrine.

Eight new emodin derivatives that contain large conjugative system have been synthesized and their anticancer activities also have been evaluated. The result shows that large conjugative system can not enhance the anticancer activities of emodin derivatives, but the introduction of an alkylating center can make emodin derivative effective against cancer cell lines. Compound 12 has the highest alkylating ability, but its anticancer activity is not remarkable, which indicates that there is not a direct correlation between the chemical reactivity of the alkylating agent and the toxic effects.

A series of substituted 2-(6-methoxynapthalen-2-yl) propanoic acid (naproxen) analogs were synthesized. (S)- naproxen (1) was treated with thionyl chloride to yield acid chloride (2) which was then reacted with different heterocyclic moieties and aryl acids to yield the (S)-naproxen analogs (3a-k). All the compounds were screened for antiinflammatory activity using in vivo rat paw oedema model and most of the active ones were investigated for their ulcerogenic potential. In silico studies (molecular modeling and docking) were carried out to recognize the hypothetical binding motif of the title compounds with the cyclooxygenase isoenzymes (COX-1 and COX-2) employing Maestro (Version 9.1, Schrodinger, LLC.) software. 2-(1-(2(2-methoxynaphthalen-6-yl)propanoyl)-1H-indol-2-yl) acetic acid (3k) was found to be the most active compound amongst the series with inhibition of paw edema volume by 62.1%, in silico sitemap score of -0.40kcal/mol and ulcerogenic index as least as 1.19.

The application of ligand-based drug design methods such as quantitative structure–activity relationship (QSAR) is a mandatory issue in the design of luteinizing hormone-releasing hormone (LHRH) receptor antagonists because the lack of information on the molecular structure for this target protein. The relationship between the structures and the antagonistic activities of 128 non-peptide antagonists for the LHRH receptor were modeled by using the classic QSAR methods comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best model included CoMSIA steric, electrostatic, hydrophobic and hydrogen bond donor fields, had a Q² value of 0.780 and predicted adequately the activity of external compounds. The tridimensional contour maps generated were used to identify the key structural requirements responsible for a high biological activity of the compounds. These features should represent the ligand features involved in interactions with the target protein that modulate their potency as antagonists.

A series of novel imidazole incorporated semicarbazones was synthesized using an appropriate synthetic route and characterized by spectral analysis (IR, ¹H NMR, ¹³C NMR and Mass). The anticonvulsant activity of the synthesized compounds was determined using doses of 30, 100, and 300 mg kg^-1 against maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) induced seizure and minimal neurotoxicity test. Six compounds exhibited protection in both models and 2-(1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene)-N-p-tolylsemicarbazone emerged as the most active compound of the series without any neurotoxicity and significant CNS depressant effect. Liver enzyme estimations (SGOT, SGPT, Alkaline phosphatase) of the compound also showed no significant change in the enzymes levels. Moreover, it caused 80% elevation of γ-amino butyric acid (GABA) levels in the whole mice brain, thus indicating that it could be a promising candidate in designing of a potent anticonvulsant drug.

A series of pyrimido[4,5-b]quinoline-2,4-dione derivatives was synthesized and evaluated for their cytotoxic activities in vitro against five human cancer cell lines. Selected compounds were tested for their MDM2 E3 ligase inhibitory activities and p53-MDM2 binding inhibitory activities. Among tested compounds, four sulfur-containing compounds (4-7) displayed enhanced cytotoxic activities and better MDM2 E3 ligase inhibitoty activities in comparison with that of HLI98c. Three compounds (4-6) showed better p53-MDM2 binding inhibitory potency with IC50 values ranging from 1.3 μM to 9.0 μM.

Benzophenonehydrazone Schiff bases 1-25 were synthesized and their in vitro antiglycation potential has been studied. Out of twenty-five compounds, thirteen showed varying degrees of antiglycation activity with IC50 values ranging between 25.7 - 305 μM, if compared with the standard rutin (IC50 = 70.5 ± 0.50 μM). Compounds 21 (2,3- dihydroxybenzaldehyde N-(diphenylmethylene)hydrazine) IC50 = 25.7 ± 0.003 μM, 14 (diphenylmethanone N-[1-(2,4- dihydroxy-5-nitrophenyl)ethylidene]hydrazine) IC50 = 36.6 ± 0.004 μM, 6 (3,4-dihydroxybenzaldehyde N- (diphenylmethylene)hydrazine) IC50 = 49.5 ± 0.001 μM, 13 (diphenylmethanone N-[1-(2,5-dihydroxyphenyl)ethylidene] hydrazine) IC50 = 52.6 ± 0.023 μM, and 15 (diphenylmethanone N-[1-(3,4-dihydroxyphenyl)ethylidene]hydrazine) IC50 = 57 ± 0.002 μM, showed showed much better antiglycation potential superior to the standard rutin. The compounds 7 (2,5- dihydroxybenzaldehyde N-(diphenylmethylene)hydrazine) IC50 = 66 ± 0.002 μM, and 25 (diphenylmethanone N-[1-(2,5- dihydroxyphenyl)propylidene] hydrazine) IC50 = 67.9 ± 0.001 μM showed compareably good antiglycation activity to standard rutin. All compounds were characterized by spectroscopic techniques and gave satisfactory elemental analysis.

In order to generate hybrid antimicrobial remedies with novel mode of action, two series of quinoline based 1,3,4-oxadiazole derivatives condensed with N-aryl/benzothiazolyl acetamides were synthesized and the MIC values of the compounds towards eight reference bacterial strains (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, S. flexneri), four fungi (A. niger, A. fumigatus, A. clavatus, C. albicans) and Mycobacterium tuberculosis H37Rv were assayed in vitro. Quinoline-6-carboxlic acid was treated with thionyl chloride in refluxing methanol to obtain the corresponding ester derivative to be hydrazinolyzed by 99% hydrazine hydrate in ethanol to produce carbohydrazide intermediate. The carbohydrazide precursor underwent cyclization by carbon disulfide and ethanolic KOH to construct 5-quinolinyl-6-yl-1,3,4-oxadiazol-2-thiol. Substituted 2-chloro-N-phenyl(benzothiazolyl)aceta-mide derivatives were then condensed to 1,3,4-oxadiazole nucleus via sulphur linkage to yield the desired products. Target products bearing N-benzothiazolyl-2-chloroacetamides displayed good inhibitory potential. The biological screening identified that many final analogues exhibited a significant inhibition of the growth of microorganisms at 3.12-25 μg/mL of MIC, which were comparable to control drugs. The influence of the presence of various functional groups to the phenyl/benzothiazolyl ring on activity profiles was investigated. The proposed structures of the newly prepared products were confirmed with the aid of IR, ¹H NMR, ¹³C NMR spectroscopy and elemental analysis. These results may provide new insights in the design of a novel pool of bioactive templates.

Computational tools of analysis were used on a set of synthetic chromone containing sulfonamide derivatives for evaluation of their enzyme inhibitory activity against Carbonic Anhydrase (CA) isozymes. GOLD docking software was utilized to dock the compounds against two human Carbonic Anhydrase (hCA) proteins; hCAII and hCA-IX. Differences in conformation and orientation of molecules within hCA-II and hCA-IX binding pockets were studied in detail which revealed that compounds with fluorine at R¹ position and phenyl sulfonamide substituent at para position served as potent inhibitors against both proteins due to anomalous chemistry of fluorine atom. It was also noticed that the activity was decreased when sulfonamide moiety was shifted from para to meta position since it dragged the interacting specie of compounds away from Zn metal. Similarly, when substituents were replaced by F > Br > C2H5 > H, the activity declined due to the electronegativity effect. Binding interaction results against CA-IX seemed to be better than CA-II due to large binding cavity, predicting the more potent inhibitory activity against hCA-IX.

Some unnatural chalcones (1a-q) and flavones (2a-d) have been synthesized and evaluated for their antiinflammatory activity using carrageenan-induced rat paw edema assay. The flavone 2c (6-Chloro-7-methyl-3', 4'- dimethoxyflavone) had higher anti-inflammatory activity and superior gastrointestinal safety profiles than the reference drug celecoxib. Compound 2c showed almost two times better selective inhibitory activity towards COX-2 enzyme than celecoxib. 2'-Hydroxychalcones (1a-h) showed moderate to strong anti-inflammatory activity (38.6-82.4 % at 3h and 52.4-80.2 % at 5h). Among 2'-methoxychalcones (1i-q) 1k and 1q exhibited maximum activity 82.6% (at 3h) and 84.3% (at 5h) respectively.

The nature has provided abundant natural resources which can be explored for their medicinal uses. The present study was undertaken to investigate the antidiabetic and hypolipidemic activity of various extract’s fractions obtained from mycelia of seventeen endophytic fungi in different solvents (methanol, acetone and aqueous) isolated from Salvadora oleoides Decne (Salvadoraceae) in glucose loaded fasting and alloxan induced diabetic Wistar albino rats. Only four extracts namely; unidentified fungus (aqueous), Aspergillus sp.JPY2 (methanol), Aspergillus sp.JPY1 (methanol) and Phoma sp. (acetone) significantly reduced blood glucose levels as revealed by glucose tolerance test. It has been observed that in alloxan induced diabetic rats, the maximum reduction in blood glucose level was after 5 hours in the acute treatment experiment and on14^th day in sub acute treatment at a dose of 250mg/kg of body weight (P<0.05). The reduction in blood glucose in long term treatment experiment was ranged from 11.3% to 28.04%, whereas standard drug tolbutamide reduced the blood glucose level up to 40%. In long term treatment, unidentified fungus (aqueous) extract showed significant improvement in parameters like body weight and lipid profile of alloxan induced diabetic rats. The gas chromatography mass spectrometer (GCMS) analysis of bioactive fraction (aqueous) of unidentified fungus and methanolic extract fraction of Aspergillus sp.JPY1 revealed that the main constituents were 2, 6-di-tert-butyl-p-cresol and Phenol, 2, 6-bis (1, 1-dimethylethyl)-4-methyl respectively. The results have also suggested that the above four bioactive fractions have good margin of safety and did not show any lethal effects on the animals up to the doses of 1000mg/kg b.w. along with safe doses up to 500 μg/ ml to human erythrocytes.