Medicinal Chemistry - Volume 7, Issue 6, 2011

α-Glucosidase is one of the important enzymes in glucose digestion and its inhibitors are known to possess a large number of therapeutic effects. In this present investigation, we have performed structural feature analysis of some of these inhibitors namely, chromenone derivatives using the Molecular Operating Environment (MOE) software. The results of the QSAR study show that the derived models are statistically significant and were validated by external (test set) and internal (leave one out) methods. The crossvalidated correlation coefficients (Q2) of the models show that the training and test sets have the values >0.6687. The physicochemical descriptors contributed for the models building in training set and complete data set show that the log of aqueous solubility (LogS) and the molar refractivity on the van der Waals surface area of the molecules (SMR_VSA4) positively contributed for the inhibitory activity. Further, the study also reveals that the polarizability and hydrogen bond acceptor/donor groups are important for the α-glucosidase inhibitory activity and these results are in agreement with the earlier studies obtained in our laboratory on α-glucosidase inhibitors which have shows that the polar surface area of the molecule is important for the interaction. The pharmacophore contours of the molecule also showed the importance of the polar surface property on the molecules. This computational analysis will help in the development of novel α-glucosidase inhibitors for various diseases.

Twenty-four 2-azetidinone derivatives have been designed and synthesized as cholesterol absorption inhibitors. All new compounds were evaluated for their activity to inhibit cholesterol absorption in hamsters, and most of them showed considerable effects in lowering the levels of total cholesterol in the serum, especially compound 2d, 4a, 4f, 4i and 4j.

Phosphodiesterase-4 (PDE 4) enzyme has emerged as an invaluable target for the treatment of asthma, chronic obstructive pulmonary disease and rheumatoid arthritis. These findings have generated widespread interest in PDE-4 inhibitors as a potential molecular target for the development of new anti-inflammatory drugs. A series of N-substituted cistetra- and cis-hexahydrophthalazinone derivatives have been reported as novel, selective PDE-4 inhibitors with potent anti-inflammatory activity. In order to gain further insights into the structural requirements of novel series of Nsubstituted cis-tetra and cis-hexahydrophthalazinone derivatives as PDE-4 inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) was performed using Genetic Function Approximation (GFA). The QSAR model was generated using a training set of 45 molecules and the predictive ability of the resulting each model was assessed using a test set of 9 molecules. The internal and external consistency of final QSAR model was 0.675 and 0.750 respectively. Analysis of results from the present QSAR study indicates that shape and structural descriptors strongly govern the PDE-4 enzyme inhibitory activity. This QSAR study highlights the structural features required for PDE-4 enzyme inhibition and may be useful for design of potent PDE-4 inhibitors.

A quantitative structure-activity relationship (QSAR) study has been made on a series of 4-chloro-N-(4- oxopyrimidin-2-yl)-2-mercaptobenzenesulfonamides. The activities of the compounds were reported against 3'-processing and the strand transfer processes catalyzed by the enzyme HIV-1 integrase. By a multiple regression, the activity against 3'-processing is found to be significantly correlated with hydrophobic and surface tension properties of the molecules and that against strand transfer with only hydrophobic property of the molecules and an indicator variable. Thus the results indicate that the hydrophobic property of the molecule plays a crucial role in the inhibition of both the 3'-processing and the strand transfer processes. The surface tension of the molecule is also shown to have some effect on inhibition of 3'- processing.

A practical synthesis of 2,3-diarylated 2H-benzo[e][1,2]thiazine 1,1-dioxides and their 3,4-dihydro derivatives was developed. ortho-Methyl lithiation of N-aryl-o-toluenesulfonamide followed by reaction with aryl aldehydes gave carbinol sulfonamides, which were either converted directly, or first oxidized to their ketones and converted, to 2,3-diarylated six-membered benzosultams via a TMSCl-NaI-MeCN mediated cyclization. A library of benzosultams was synthesized and evaluated for inhibitory activity against MCF-7 cells. Compound 3 in the 3,4-dihydro (saturated) series and compound 8 in the unsaturated series exhibited the highest potencies with growth inhibition (GI50) values of 0.8 and 18.0 μM, respectively. Molecular modeling studies suggest that these compounds can associate with the colchicine binding site on microtubules. However, experimental assessments of that and other mechanistic possibilities are still ongoing.

2,4,6-Trichlorophenyl hydrazones 1-35 were synthesized and their in vitro antiglycation potential was evaluated. Compounds 14 (IC50 = 27.2 ± 0.00 μM), and 18 (IC50 = 55.7 ± 0.00 μM) showed an excellent activity against glycation of protein, better than the standard (rutin, IC50 = 70 ± 0.50 μM). This study thus identified a novel series of antiglycation agents. A structure-activity relationship has been studied, and all the compounds were characterized by spectroscopic techniques.

Soluble Epoxide Hydrolase (sEH) is an important and promising new pharmacologic target for the treatment of acute systemic inflammation. Inhibition of sEH by a highly selective and potent sEH inhibitor (sEHI) elevates the epoxyeicosatrienoic acids (EETs) level in vivo leading to decreased inflammation. To explore the necessary structural requirement of 1, 3-disubstituted ureas as sEH inhibitors for anti-inflammatory activity, the molecular modeling studies have been pursued. A ligand-based pharmacophoric model and atom-based 3D-QSAR have been generated by Phase. Binding interaction as determined by the docking study revealed that these inhibitors interact at active site (ASP 335 & TYR 383) of sEH enzyme. The pharmacophore model was further used as a 3D query for virtual screening to retrieve potential inhibitors.

Development of drug resistance and the presence of dose-limiting side-effects remain the two main problems in cancer chemotherapy. Combination of drugs with different mechanisms of action can offer a distinct advantage over monotherapy in overcoming drug resistance and reducing the side-effects. In this study synergism in activity from the combinations of cisplatin (Cis) with two multicentred platinum complexes coded as TH1 and DH6Cl in the human ovarian A2780, A2780cisR and A27800473R cancer cell lines had been investigated. Although Cis, TH1 and DH6Cl all bind with nucleobases in the DNA, they differ in the nature of adducts formed and the non-covalent interactions they may undergo. Whereas Cis binds with nucleobases in the DNA forming mainly intrastrand bifunctional adducts such 1,2-Pt(GG) and 1,2-Pt(AG), TH1 and DH6Cl are expected to form mainly interstrand bifunctional G-Pt…..Pt-G adducts with the DNA. It was found that Cis in combination with TH1 and DH6Cl produced both sequence- and concentration-dependent synergism. Generally greater synergism was produced when the two compounds were added at the same time than with a 4 h time gap. For the combination of Cis with TH1, significant synergism was produced only in the parent A2780 cell line but not in the resistant A2780cisR and A27800473R cell lines, thus indicating that the combinations of Cis with TH1 would not offer any advantage in overcoming the drug resistance. In contrast, 0/0 h and 4/0 h combinations of Cis and DH6Cl in A2780cisR cell line were found to be synergistic, thus indicating that combinations of Cis with DH6Cl may offer a therapeutic advantage. Although both TH1 and DH6Cl are expected to form a number of long-range interstrand G-Pt……Pt-G adducts with nucleobases in the DNA, TH1 and DHCl are expected to differ in their non-covalent interactions with the DNA due to the presence of two 3-hydroxypyridine ligands bound to the central metal ion in TH1 but not in DH6Cl which instead contains two ammino ligands bound to the central palladium ion.

A series of twenty-one 7-chloro-4-quinolinylhydrazones derivatives (3a-u) have been synthesized and evaluated for their cytotoxic potential against three cancer cell lines using MTT assay. The compounds 3b, 3e, 3f, 3h, 3j, 3n, 3r and 3u displayed more than 90% of growth inhibition (GI) and they were selected for in vitro anticancer activities evaluation against four human cancer cell lines. These results were expressed as the concentrations that induce 50% inhibition of cell growth (IC50) in μg/mL. Considering that, compounds 3b, 3e, 3h, 3n, 3r and 3u exhibited good cytotoxic activity against at least three cancer cell lines (0.7967- 4.200 μg/mL). In general, we observed that the presence of electronwithdrawing groups in the benzene ring is important for the anticancer activity in this series, such as fluorine (3h), chlorine (3b) amd bromine (3e) groups in meta position and nitro group (3r) in para position. These derivatives could be considered interesting start points to develop a new anticancer drug and confirm the potential of chloroquine derivatives as lead compounds in anticancer drug discovery.

Ten novel 3-(2-(3-methyl-5-substituted-phenyl-4,5-dihydropyrazol-1-yl)-2-oxo-ethoxy)-2-substituted-phenyl- 4H-chromen-4-one derivatives were synthesized and characterized by 1H NMR and 13 C NMR. All of the compounds have been screened for their anticancer activity. The bioassay tests show that compound 6af exhibited potentially high activity against human gastric cancer cell SGC-7901 with IC50 value of 4.01±0.97 μg/mL. Also, the title compounds were assayed for telomerase inhibition. The results show that compounds 6cf, 6af can strongly inhibit telomerase with IC50 values of 4.89±0.11 and 5.02±0.91 μM, respectively. Docking simulation was performed to position compound 6cf into the telomerase (3DU6) active site to determine the probable binding model.

A series of 32 L-serinyl hydrazone derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv, being also evaluated their cell viabilities in non infected and infected macrophages with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). The compounds 8c, 8e, 8h and 8i, were non-cytotoxic and exhibited an important minimum inhibitory concentration (MIC) activity between 25 and 100μg/mL, which can be compared with that of the tuberculostatic drug D-cicloserine (5-20μg/mL).

A series of D-glucuronic acid derivatives were chemically synthesized including acetylated and deacetylated glucuronamides, as well as N-glucuronides starting from the D-glucuronic acid itself by means of protection/deprotection, activation and condensation protocols. Structure elucidation of all products along with optimization of the synthetic steps is described. The synthesized compounds were evaluated for their in vitro antitumor activity against MCF-7, TK-10 and UACC-62 cell lines. The compounds 4, 5, 7, 8, 14, 16 and 18 were the most active against TK-10 cell line. On the other hand, the most active compounds against the MCF-7 cell line were 9, 18 and 20. However, compounds 7-10 13-15 and 17 were the most active against the UACC-62 cell line.

In this study, the screening of five anthraquinones (purpurin, xanthopurpurin, rubiadin, kermisic acid and flavokermisic acid), for their free radical scavenging and antioxidant effects was carried out, using three complementary methods. DPPH (2,2'-diphenyl-1-picrylhydrazyl) revealed that purpurin has a scavenging effect with IC50 = 3.491 ± 0.014 ??g/ml. Results of β-carotene / linoleic acid assay showed that kermisic and flavokermisic acids have significant inhibition of lipid peroxidation with I % = 76.1 ± 1.5 % and 68.6 ± 2.5 %, respectively. In addition, the ferrous ion chelating test showed that only purpurin, with small concentrations, interferes in a dose dependant manner with the formation of Fe2+- ferrozine complex. These results are promising for further studies of the biological and pathological effects of these natural products.

The antimalarial activities of a series of 2-aziridinyl and 2,3-bis-(aziridinyl)-1,4-naphtoquinonyl sulfate and acylate derivatives have been modeled using multivariate image analysis (MIA) descriptors. The two-dimensional chemical structures correlated reasonably well with dependent variables (Y block) through partial least squares - PLS (for the unfolded data) and multilinear partial least squares - N-PLS (for the three-way array). However, the use of PCA-ranking as variable selection method and least-squares support vector machines (LS-SVM) as regression method improved significantly the prediction ability of the model. All models were validated through leave-one-out and leave-25%-out crossvalidations, as well as by means of a Y-randomization test, and demonstrated advantages in prediction performance over an existing model, in which descriptors related to physicochemical and geometric properties of molecules were used to derive multiple linear regression (MLR) and artificial neural networks (ANN) based models. Accounting for non-linearity seems to be an important task for the QSAR modeling of bioactivities of the studied antimalarial compounds.

Ribavirin and its 553 analogues have been docked with NS5-methyltransferase of Dengue viruses using Glide- HTVS and Glide-XP computational tools and the compounds have been screened based on their Glide-Gscores to identify lead ribavirin analogues that may act as inhibitors to the enzyme. Upon studying the interactions of ribavirin triphosphate (RTP) and triphosphate of lead ribavirin analogues with NS5-methyltransferase and Janus tyrosine Kinase-2 (JAK2) enzymes using molecular docking and dynamic methods, the possible mechanism by which the ribavirin causes haemolytic anaemia has been proposed. De novo RTP-analogues showing stronger affinities with NS5-methyltransferase and weaker affinities with JAK2 have been designed. The essential structural features of the de novo RTP-analogues for developing them as specific antiviral drugs against the infections due to dengue viruses have been discussed in detail.

A series of novel 2-[4-aryl-5-{(quinolin-8-yloxy)methyl}-4H-1,2,4-triazol-3-ylthio]-1-arylethanones (6a-6j) and 8-{(5-aryl-1,3,4-oxadiazol-2-yl)methoxy}quinolines (7a-7d) were synthesized from the corresponding 4-arnyl-1-(2- quinolin-8-yloxy)acetyl) thiosemicarbazides (4a-4d) and hydrazides (3) respectively. The prepared compounds were screened for their anti-inflammatory, analgesic, ulcerogenic and antimicrobial activities. The anti-inflammatory activities were determined by carrageenan induced rat paw edema method. Compounds 6c, 6d, 6f 6j, 7b and 7e significantly inhibited the rat paw edema depending upon the dose employed. These compounds exhibited insignificant ulceration compared to the standard drug Indomethacin. The compounds were also evaluated for their in vitro antimicrobial activity. Some compounds have shown moderate to good activity whereas compound 7b has shown significant zone of inhibition compared to the standard drug Ampicillin against Gram negative microorganisms.

Strong antiseptic activity of essential oils has been known for a long time. The antibacterial activity of oils was tested against clinical bacterial strains of Staphylococcus, Enterococcus, Escherichia and Pseudomonas genera. The agar diffusion method was used for microbial growth inhibition at various concentrations of the oils from T. vulgaris and L. angustifolia. Susceptibility testing to antibiotics and chemotherapeutics was carried out using disc-diffusion method. 120 strains of bacteria isolated from patients with infections of oral cavity, respiratory, genitourinary tracts and from hospital environment were investigated. The results of experiments showed that the oil from T. vulgaris exhibited extremely strong activity against all of the clinical strains. Thyme oil demonstrated a good efficacy against antibiotics resistant strains of the tested bacteria. Lavender oil has been less activity against clinical strains of Staphylococcus, Enterococcus and Escherichia genus. The worst results have been observed against all strains of Pseudomonas aeruginosa.

In this study novel thiosemicarbazides bearing piperidine moiety were synthesized in order to investigate their possible antibacterial and antifungal activities. A structure-activity relationship (SAR) study including conformational analysis and some physicochemical descriptors was carried out to provide the guidance for further synthetic work. The significant molecular descriptors related to the compounds with antifungal activity were: electrostatic potential surface, the highest occupied molecular orbital energy, surface area, volume, and hydration energy.

N-substituted 3-amino-5-hydroxy-4-phenyl-1H-pyrazole-1-carboxamide derivatives have been prepared by heterocyclization of 1-cyanophenyl acetic acid hydrazide with isocyanates. Representative compounds were evaluated as potential antimicrobial agents. The most promising compound in this series, the N-(1-naphthyl)-3-amino-5-hydroxy-4- phenyl-1H-pyrazole-1-carboxamide 2f, was the most effective against the reference strains of pathogenic S. aureus ATCC 25923 and S. aureus ATCC 6538 or opportunistic S. epidermidis ATCC 12228 with MIC value of 7.81 μg/ml and against the other Gram-positive species with MIC values 15.63-31.25 μg/ml. This compound also showed high activity against clinical isolates of MSSA (methicillin-sensitive Staphylococcus aureus) with MIC of 0.98 - 31.25 μg/ml and MRSA (methicillin- resistant Staphylococcus aureus) with MIC of 1.96 - 7.81 μg/ml.

Disulfides 1-30 have been synthesized and their in vitro leishmanicidal activity has been evaluated. Compounds 18 (IC50 = 2.70 ± 0.044 μM), 19 (IC50 = 2.85 ± 0.02 μM), 20 (IC50 = 2.92 ± 0.01 μM), 26 (IC50 = 3.69 ± 0.01 μM), 21 (IC50 = 4.45 ± 0.029 μM), and 29 (IC50 = 4.46 ± 0.025 μM) showed a remarkable leishmanicidal activity if compared with standard pentamidine (IC50 = 5.09 ± 0.04 μM). This study has discovered a series of possible molecules as antileishmanial agents. A structure-activity relationship study has also been carried out. The structures of all the synthesized compounds were identified by using spectroscopic techniques, including 1H-NMR and EI MS.