Letters in Drug Design & Discovery - Volume 10, Issue 7, 2013

This study evaluated and compares the antioxidant activity of six resveratrol analogues. The analogues 4’- Hydroxyphenyl-benzo[d]thiazole (A), p-(N,N-dimethyl)aminobenzylidene-2-aminothiophenol (B) and p-Nitrobenzylidene- 2-aminothiophenol (C) were synthesized and the antioxidant activity was evaluated using the DPPH method. A descriptive statistical analysis and ANOVA followed by the Tukey test, with the aid of software. The best antioxidant activity was demonstrated by compound C (half maximal inhibitory concentration (IC50) = 18.45µM), this compound is two times more active than resveratrol (IC50= 37.28µM). Taken together, the data presented herein suggest that these molecules might serve as potential antioxidant considering that molecular modification is an effective strategy. As such, the compounds described herein can serve as prototypes for further research and the development of novel antioxidant agents.

A series of novel hybrid compounds between tricyclic indeno[5,6-b]furan and imidazole has been prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the existence of benzimidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl group were vital for modulating cytotoxic activity. In particular, hybrid compound 26 was found to be the most potent compound against 5 strains human tumor cell lines and more active than cisplatin (DDP), while compound 18 was more selective towards breast carcinoma (MCF-7) and colon carcinoma (SW480) with IC50 value 3.4-fold and 4.3-fold more sensitive to DDP.

Quantitative structure–activity relationship studies have been performed on twenty one β-carboline derivatives to investigate the structural requirements for antitumor activity. The best 2D-QSAR model (r2 = 0.802, F = 24.321, r2se = 0.325) indicated statistical significance and internal predictivity of the developed model shown by the value of cross validated squared correlation coefficient which was 0.724. A five-point pharmacophore hypothesis yielded ligand based pharmacophore 3D-QSAR models with good partial least-square (PLS) statistics results. The training set and test set correlation was characterized by PLS factors (r 2 = 0.842, SD = 0.306, F = 21.3, P = 4.27e -05, Q2 ext = 0.748, RMSE = 0.531, Pearson-R = 0.975). A docking study revealed the binding orientations of DNA intercalates at active site of amino acid residues. The results of 2D-QSAR and 3D-QSAR give detailed structural insights and at the same time highlight the important binding features of novel β-carboline derivatives as antitumor agents.

An efficient synthesis of novel AZT derivatives possessing Mannich base moieties via click chemistry is described. Firstly, the reaction of ferulic acid (1) with propargyl bromide and propargyl amine gave intermediates 2 and 3, respectively. Secondly, the Mannich reaction of 2 and 3 with secondary amines in ethanol under reflux conditions furnished two series of novel Mannich bases 2a-h and 3a-h in good yields. Finally, title compounds 5a-h and 6a-h were obtained via click reaction of 2a-h and 3a-h with 3’-Azido-2’-deoxythymidine (AZT) in moderate to good yields. Novel Mannich bases and AZT derivatives were evaluated for in vitro cytotoxic activity against three cell lines: MDA-MB-231, SK-LU-1, and SW480. The result showed that AZT derivatives were inactive to three cell lines, while Mannich bases exhibited cytotoxic activity against three cell lines, in which compound 2g is found to be the most potent cytotoxic activity against MDA-MB-231 cell line with IC50 values of 19.96 µg/mL.

A few celecosib like 1,5-diarylpyrazoles conjugated with nitric oxide (NO) donating nitrate ester group were synthesized and evaluated for their selective COX-2 inhibitory activity along with NO releasing ability of corresponding nitrate esters. Most of the synthesized compounds exhibited improved COX-2 inhibition when compared with the reference drug celecoxib. The nitrate ester derivatives (coxib prodrugs) 7 (nitrate ester of 1,5-diarylpyrazole with 2 carbon linker), and 9 (nitrate ester of 1,5-diarylpyrazole with 3 carbon linker), upon incubation in human whole blood were partly transformed into the corresponding alcohols 6, and 8 respectively. Molecular docking studies were performed on alcohol derivatives and revealed additional H-bond interactions compared to celecoxib.

Diabetes mellitus is a chronic metabolic disease affected a wide range of population all over the world and leads to development of many severe long term complications. Aldose reductase (AR) is the enzyme considered to play a key role in the development of secondary diabetic complications via polyol pathway. AR inhibition has been proposed as a strategy to prevent and delayed such complications. 2,4-thiazolidinedione derivatives being isosteres of hydantoin, emerged as potential AR inhibitors with antidiabetic activity. Therefore, we have designed novel arylidene-2, 4-thiazolidinediones as AR inhibitors using molecular docking technique. Mol-dock score along with re-rank score was the criteria for measuring the affinity of STMG-(1-40) with the AR enzymes. Result of present study will provide a new guideline for the further design of novel potent inhibitors of AR in the management of diabetes along with its complications.

Dihydrocumic acid was prepared from β-pinene through oxidation and dehydration. Then a series of amide derivatives from dihydrocumic acid were synthesized. Reaction conditions of dihydrocumic acid were discussed and structures of amide derivatives were characterized by IR, 1H NMR, MS, and X-ray diffraction. The antibacterial activities of these newly synthesized amide derivatives against six bacteria were also investigated by an inhibition zone method. It was shown that compounds 5a, 5b, 5d, and 5f display better anti-bacterial activities with inhibition zones 11.83, 12.33, 10.83 and 12.67 mm against Escherichia coli compared with Bromogeramine (9.67 mm), one commercially available antibacterial agent, and compounds 5a and 5d display better anti-bacterial activities against Staphyloccocus aureu compared with Ampicillin Na.

Hydrazones are important classes of compounds found in many synthetic products. Due to their importance in synthetic chemistry, the present article reports the synthesis of twelve new hydrazone derivatives based on the coupling of 2,5-difluorobenzohydrazide with different benzaldehydes and screened for their antibacterial activities at the concentration 250 µg/mL with reference to the standard antibacterial drug Ampicillin. The screening results revealed that hydrazone derivatives 4d, 4e, 4f and 4h having fluorine substitution showed significant antibacterial activity comparable to that of standard drug Ampicillin.

Amine coupling strategy was developed for the synthesis of new indazole derivatives through reaction of 4-(3- (4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) benzoic acid 19 with amines 20a-i. All the newly synthesized compounds were screened for their antimicrobial and antifungal activities. Among the several compounds synthesized (4-(3-(4-hydroxyphenyl)-1H-indol-5-yl)phenyl)(piperazin-1-yl)methanone 2, (4-(3-(4-hydroxyphenyl)-1Hindazol- 5-yl)phenyl)(4-methylpiperazin-1-yl)methanone 3, 1-(4-(4-(3-(4-hydroxyphenyl)-1H-indol-5-yl) benzoyl) piperazin- 1-yl) ethanone 4 and (4-(3-(4-hydroxyphenyl)-1H-indol-5-yl) phenyl)(pyrrolidin-1-yl)methanone 9 showed potential activities against a variety of bacterial and fungal strains.

A novel series of 4-(arylideneamino)-N’-((2-chloro-8-methylquinolin-3-yl)methylene)-3-phenyl-2-thioxo-2,3- dihydrothiazole-5-carbohydrazides (5a-o) bearing biologically active 2-chloroquinoline-3-carbaldehyde and 2-thioxothiazole ring have been synthesized. The structures of synthesized compounds were established by spectroscopic techniques (IR, 1H NMR, 13C NMR and mass spectrometry). Antimicrobial screening of compounds (5a-o) was done against Gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus niger and Aspergillus clavatus) using serial broth dilution method. SAR for the series was developed by comparing their MIC values with ampicillin and griseofulvin. Some of the compounds from the series like 5o were found to be most active at MIC 12.5 µg/mL against P. Aeruginosa, and compound 5k was found to be most active at MIC 12.5 µg/mL against A. clavatus.

Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis (M. tuberculosis), and remains one of the most life-threatening plagues for public health in the world. The emergence of drug resistant strains of TB and co-infection with HIV has further complicated TB treatment. Here, the synthesis and characterizaton of a series of compounds were described, and these were followed by evaluating for their antibacterial activity against M. tuberculosis. Several novel arylthiourea derivatives exhibited excellent activity (lowest MIC=0.09 µg/ml) against M. tuberculosis including drug resistant strains of M. tuberculosis. The results suggest that these compounds are promising candidates for new anti-TB agent development.

Some 6-Phenyl/Biphenyl-4-yl-2-[2-(pyridin-2-ylamino)-ethyl]/-2-(2N-subtituted amin-1-yl)-ethyl-4,5- dihydropyridazin-3(2H)-one (4a-h) were synthesized by reacting 6-phenyl/biphenyl-4,5-dihydropyridazin-3(2H)-one with bromoethyl derivatives of cyclic secondary amines and 2-aminopyridine. All the compounds, 4a-h, were evaluated as anticonvulsant by using maximum electro shock (MES) and isoniazid (INH) induced convulsion methods at 50mg/kg dose level, and as antitubercular by Microplate Almar Blue Assay (MABA) method. In anticonvulsant activity, phenytoin (25mg/kg) and sodium vaproate (50mg/kg) were used as reference drugs. All compounds (4a-h) showed significant anticonvulsant activities against both MES and INH methods, and compound g showed highest activity against MES method. In antitubercular activity, compounds 4c-4h showed 25 &microg/ml MIC value, and compounds 4a-4b exhibited 50 µg/ml MIC value when compared with reference drugs [isoniazid (3.125 µg/ml), pyrizinamide (3.125micro;g/ml)] and (streptomycin 6.25µg/ml) MIC values, and found less potent than the reference drugs.

Parsol 1789 and eusolex 8021 are two 1,3-diarylpropane-1,3-diones widely used as UV-absorbing agents in sunscreen formulations. Their chemical structures are quite similar to that of curcumin, a natural compound known to present a wide range of relevant pharmacological activities, including antifungal and anticancer activities. Such structural similarity, together with their availability and low cost sparked our interest for investigating their potential as antiproliferative and antifungal agents. Parsol and eusolex presented antiproliferative activity against eight human cancer cell lines. Promisingly, parsol was almost as active against the human lung cancer cell line NCI-ADR/RES (GI50 1.1± µg mL-1) as the positive control doxorubicin (GI50 1.7±2.1 µg mL-1). When tested for antifungal activity, parsol and eusolex showed activity comparable to that of fluconazole, the reference drug, against Paracoccidioides brasiliensis and Cryptococcus neoformans. Sporothrix schenckii was significantly more sensitive to parsol and eusolex (MIC = 16 µg mL-1, for both compounds) than fluconazole (MIC = 64 µg mL-1)

A quantitative structure-activity relationship study has been made on two different series of nitric oxide synthase (NOS) inhibitors. A series of imidazoles and some mono or bicyclic nitrogen-containing heterocycles was reported to potently act against neuronal NOS (nNOS) and a series of 2-aminopyridines to act against inducible NOS (iNOS). The QSAR model derived for the former suggested that nNOS inhibition activity of the compounds is basically controlled by electronic nature of the molecule and that the compounds having fused ring would have added advantage and the one derived for the latter suggested that iNOS inhibition activity of 2-aminopyridines is controlled by hydrophobic nature of 6- substituents and the steric nature of 4-substituents. A negative effect on activity in this series was however suggested to be produced by the polarizability of the molecule.