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A series of new 2-methyl-2-[(1,3-Diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]-N- substituted arylacetamides were synthesized. The antitumor activity of these purine based compounds were evaluated on breast cancer (MCF7) and leukemic cancer (K562) cell lines via cell viability assay utilizing the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). These results were substantiated using computer docking experiments (LigandFit docking engine and PMF scoring function) which predict that the antitumor activity of these new compounds may be attributable to their abilities to effectively bind and block oncogenic tyrosine kinases, particularly bcr/abl.

The Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging virus that poses a major challenge to clinical management. The 3C-like protease (3CLpro) is essential for viral replication and thus represents a potential target for antiviral drug development. Presently, very few data are available on MERS-CoV 3CLpro inhibition by small molecules. We conducted extensive exploration of the pharmacophoric space of a recently identified set of peptidomimetic inhibitors of the bat HKU4-CoV 3CLpro. HKU4-CoV 3CLpro shares high sequence identity (81%) with the MERS-CoV enzyme and thus represents a potential surrogate model for anti-MERS drug discovery. We used 2 well-established methods: Quantitative structure-activity relationship (QSAR)-guided modeling and docking-based comparative intermolecular contacts analysis. The established pharmacophore models highlight structural features needed for ligand recognition and revealed important binding-pocket regions involved in 3CLpro-ligand interactions. The best models were used as 3D queries to screen the National Cancer Institute database for novel nonpeptidomimetic 3CLpro inhibitors. The identified hits were tested for HKU4-CoV and MERS-CoV 3CLpro inhibition. Two hits, which share the phenylsulfonamide fragment, showed moderate inhibitory activity against the MERS-CoV 3CLpro and represent a potential starting point for the development of novel anti-MERS agents. To the best of our knowledge, this is the first pharmacophore modeling study supported by in vitro validation on the MERS-CoV 3CLpro. Highlights MERS-CoV is an emerging virus that is closely related to the bat HKU4-CoV. 3CLpro is a potential drug target for coronavirus infection. HKU4-CoV 3CLpro is a useful surrogate model for the identification of MERS-CoV 3CLpro enzyme inhibitors. dbCICA is a very robust modeling method for hit identification. The phenylsulfonamide scaffold represents a potential starting point for MERS coronavirus 3CLpro inhibitors development.

A new series of N1-(flavon-6-yl)amidrazones were synthesized by reacting the hydrazonoyl chloride derived from 6-aminoflavone with the appropriate sec-cyclic amines. The antitumor activities of these compounds were evaluated on breast cancer (MCF-7) and leukemic (K562) cell lines. Among the compounds tested, the N-morpholine derivative was the most active against the MCF-7 and K562 cell lines, with IC50 values of 5.18 and 2.89 μM, respectively. Our docking studies showed that the N-morpholino derivative fits and blocks the oncogenic tyrosine kinases bcr/abl and epidermal growth factor receptor (EGFR) in a similar fashion to that of the potent anticancer agent imatinib.

Naproxen and cromolyn were investigated as new inhibitors of glycogen synthase kinase-3β (GSK-3β) in an attempt to explain their hypoglycemic properties. Study included simulated docking experiments, in vitro enzyme inhibition assay, and in vivo validations. Both drugs not only were optimally fitted within a GSK-3β binding pocket via several attractive interactions with key amino acids but also exhibited potent in vitro enzymatic inhibitory activities of IC50 1.5 and 2.0 µM for naproxen and cromolyn, respectively. In vivo experiments illustrated that both drugs significantly reduced serum glucose and increased hepatic glycogen- and serum insulin levels in normal and type II diabetic Balb/c mice models. In obese animal model, both drugs exhibited significant reduction in mice weights, serum glucose, and resistin levels along with significant elevation in serum insulin, C-peptide, and adiponectin values. It can be concluded that naproxen and cromolyn are novel GSK-3β inhibitors and can help in management of diabetes and obesity.

The fact that ethosuximide (ETO), phenobarbital (PHO), and barbituric acid (BARB) share structural and pharmacophoric homologies with phenytoin and allantoin, both known to have significant wound-healing properties, prompted us to evaluate them as wound-healing agents. Accordingly, ETO-, PHO-, and BARB-containing ointments were applied onto full-thickness excision and incision wounds created on the dorso-lumbar region of experimental rats. ETO-and PHO-treated incision wounds illustrated significant enhancement in breaking strengths (1380 ± 61 and 1240 ± 42 g, respectively) compared to vehicle controls (1070 ± 18 g) and BARB (1080 ± 45 g). Moreover, biochemical analyses revealed significant increase in hydroxyproline contents in ETO- and PHO-treated wounds compared to vehicle controls. Histological evaluation revealed that both ETO and PHO promoted collagen synthesis and deposition. This is the first time to describe the significant wound-healing merits of ETO and PHO as potential clinical agents for treatment of chronic wounds.

N-Myristoyl transferase is an essential enzyme for fungal growth and survival. The continuous interest in the development of new antifungal agents prompted recent interest in developing new potent inhibitors of fungal N-myristoyl transferase. In this context, we combined pharmacophore and QSAR modeling to explore the structural requirements for potent N-myristoyl transferase inhibitors employing 55 known N-myristoyl transferase ligands. Four binding pharmacophore models emerged in the optimal QSAR equations (R(2)(44) = 0.81-0.83, F-statistic = 47.89-58.83, r(2)(L00)= 0.77-0.80, against 11 external test inhibitors = 0.61-0.71). The successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve profiles. The QSAR equations and their associated pharmacophore models were validated by the identification and experimental evaluation of new promising antifungal leads retrieved from the NCI database and our in-house-built database of established drugs and agrochemicals.

Glycosidases, including β-D-galactosidase, are involved in a variety of metabolic disorders, such as diabetes, viral or bacterial infections, and cancer. Accordingly, we were prompted to find new β-D-galactosidase inhibitors. Towards this end, we scanned the pharmacophoric space of this enzyme using a set of 41 known inhibitors. Genetic algorithm and multiple linear regression analyses were used to select an optimal combination of pharmacophoric models and physicochemical descriptors to yield self-consistent and predictive quantitative structure-activity relationship (QSAR). Five pharmacophores emerged in the QSAR equations suggesting the existence of more than one binding mode accessible to ligands within β-D-galactosidase pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic curve profiles. The validity of the QSAR equations and the associated pharmacophoric models were experimentally established by the identification of several β-D-galactosidase inhibitors retrieved via in silico search of two structural databases: the National Cancer Institute list of compounds and our in house built structural database of established drugs and agrochemicals.

Dipeptidyl peptidase IV (DPP IV) deactivates the natural hypoglycemic incretin hormones. Inhibition of this enzyme should restore glucose homeostasis in diabetic patients making it an attractive target for the development of new antidiabetic drugs. With this in mind, the pharmacophoric space of DPP IV was explored using a set of 358 known inhibitors. Thereafter, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and physicochemical descriptors that yield selfconsistent and predictive quantitative structure-activity relationships (QSAR) (r(2) (287)=0.74, F-statistic=44.5, r(2) (BS)=0.74, r(2) (LOO)=0.69, r(2) (PRESS) against 71 external testing inhibitors=0.51). Two orthogonal pharmacophores (of cross-correlation r(2)=0.23) emerged in the QSAR equation suggesting the existence of at least two distinct binding modes accessible to ligands within the DPP IV binding pocket. Docking experiments supported the binding modes suggested by QSAR/pharmacophore analyses. The validity of the QSAR equation and the associated pharmacophore models were established by the identification of new low-micromolar anti-DPP IV leads retrieved by in silico screening. One of our interesting potent anti-DPP IV hits is the fluoroquinolone gemifloxacin (IC(50)=1.12 muM). The fact that gemifloxacin was recently reported to potently inhibit the prodiabetic target glycogen synthase kinase 3beta (GSK-3beta) suggests that gemifloxacin is an excellent lead for the development of novel dual antidiabetic inhibitors against DPP IV and GSK-3beta.

The naturally occurring polymer chitosan was reacted separately with succinic and phthalic anhydrides. The resulting semisynthetic polymers were assessed as potential matrices for colon-specific, orally administered drug delivery. Sodium diclofenac was used as the dispersed model drug. The prepared matrices were incorporated into tablets, which were evaluated in vitro. The evaluation included dissolution studies conducted under simulated gastrointestinal conditions of pH and transit times. The percentage fluid uptake was used to indicate the ability of the matrix to protect an embedded drug from gastric juices. The prepared matrices resisted dissolution under acidic conditions. On the other hand, improved drug release profiles were observed under basic conditions. Therefore, the results suggest the suitability of the prepared matrices in colon specific, orally administered drug delivery system. However, future in vivo testing is planned to fully establish the suitability of the prepared polymers for colon-specific drug delivery.

Inhibitor kappa-B kinase-beta (IKK-β) controls the activation of nuclear transcription factor kappa-B and has been linked to inflammation and cancer. Therefore, inhibitors of this kinase should have potent anti-inflammatory and anticancer properties. Accordingly, we explored the pharmacophoric space of 218 IKK-β inhibitors to identify high-quality binding models. Subsequently, genetic algorithm-based quantitative structure activity relationship (QSAR) analysis was employed to select the best possible combination of pharmacophoric models and physicochemical descriptors that explain bioactivity variation among training compounds. Three successful pharmacophores emerged in 2 optimal QSAR equations (r12175 = 0.733, r12LOO = 0.52, F1 = 65.62, r12PRESS against 43 test inhibitors = 0.63 and r22175 = 0.683, r22LOO = 0.52, F2 = 72.66, r22PRESS against 43 test inhibitors = 0.65). Two pharmacophores were merged in a single binding model. Receiver operating characteristic curve validation proved the excellent qualities of this model. The merged pharmacophore and the associated QSAR equations were applied to screen the National Cancer Institute list of compounds. Ten hits were found to exhibit potent anti-IKK-β bioactivity, out of which, one illustrates IC50 of 11.0nM.