Letters in Drug Design & Discovery - Volume 11, Issue 4, 2014

Cytotoxic activity of four O,O'-dialkyl esters of ethylene-bis(S)-leucine [(S,S)-ethylenediamine-N,N’-di-2-(4- methyl)pentanoic acid] dihydrochlorides, R2edda-type esters L1.2HCl–L4.2HCl (alkyl = Et, n-Pr, n-Bu, and n-Pe, respectively), and corresponding palladium(II) (1–4) and platinum(II) (5–8) complexes against MDA-MB-361, MDA-MB-453 (human breast cancer), Jurkat (T-leukemia) and K562 (chronic myelogenous leukaemia) cell lines were determined. Results indicate cytotoxic potential of the investigated complexes based on induction of apoptosis.

Two series of new ionone alkaloid derivatives were synthesized and evaluated for antitumor invasive activities in human MDA-MB-231 breast cancer cells. The structures of derivatives were elucidated by 1H, 13C NMR and mass spectrometric methods. Ionone alkaloid derivatives 1a, 1c, 1d, 4i, 4j and 4k revealed significant inhibitory effects on the invasion of MDA-MB-231 cells in invasion assay, and compound 4j bearing a 4-fluoro benzene group of ionone alkaloid exhibited potent anti-invasive activity with an IC50 value of 0.054 μM.

Carbonic anhydrases XIV (CA XIV) is responsible for health issue and a therapeutic target of many disorders like epilepsy, and retinopathy. Here we described the first pharmacophore model for human CA XIV to identify the new scaffolds compounds. Hypotheses 1, with the highest cost difference, best correlation coefficient as well as the lowest RMSD, was validated by test set and Fischer method. Then, Hypotheses 1 was used for virtual screening in 718361 databases compounds. After Lipinski’s rule of five and ADMET properties, 148 compounds with high potential activity were filtered and estimated by docking. Finally, 6 new scaffold compounds turned out to be potential as new class CA XIV antagonists. In addition, we also analyzed the interaction between compound 7 and ten CA isoforms and explained various inhibitions caused by their distinct residues. Therefore, this paper could be helpful in novel CA XIV inhibitors discovery and its selective inhibitors design.

A novel series of 2,5-disubstituted-1,3,4-oxadiazole analogs (4a-j) was synthesized starting from 2-aminopyrimidine. A computational study was carried out for the molecular properties prediction and none of the compounds violated Lipinski “Rule of 5”. The structures of the compounds were confirmed on the basis of their spectral data and the purity of the compounds was checked by elemental analysis. Some of the compounds were screened for in vitro anticancer activity as per National Cancer Institute (NCI US) Protocol on leukemia, melanoma, lung, colon, CNS, ovarian, renal and prostate and breast cancer cell lines. N-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}pyrimidin-2- amine (4a) showed maximum activity with growth percent of 61.19 (UO-31; Renal cancer) and 76.82 (MCF; Brest Cancer). The antibacterial and antifungal activities were evaluated as per the standard protocol reported elsewhere. N-{[5-(4- aminophenyl)-1,3,4-oxadiazol-2-yl]methyl}pyrimidin-2-amine (4e) showed maximum antibacterial activity among the series, comparable to the standard drug ciprofloxacin with MIC ranging from 4-8 μg/mL while N-{[5-(3,4- dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}pyrimidin-2-amine (4g) showed maximum antifungal activity among the series, less active than the standard drug fluconazole with MIC 4 μg/mL.

Neuraminidase (NA) is a glycoprotein found on the surface of influenza A virus that is used for releasing new progeny of virions by cleaving the terminal sialic acid residue from the surface of infected cells. Therefore, NA is an interesting potential target to design promising NA inhibitiors to serve as antiviral agents for preventing viral propagation. In this study, a data set of 61 H1N1 neuraminidase inhibitors of influenza A virus was employed in the construction of quantitative structure-activity relationship (QSAR) model using the CORrelation And Logic (CORAL) software available at http://www.insilico.eu/coral. The chemical structure of compounds in the SMILES format was used as input to CORAL in discerning the correlation between an endpoint (i.e. neuraminidase inhibitory activity) and their corresponding molecular descriptors. Three random splits of the data into sub-training, calibration and testing sets were carried out. The optimal threshold and number of epoch to use in building the QSAR models were derived from the CORAL software. Results indicated that the QSAR models displayed good prediction performance as deduced from statistical parameters affording r2 = 0.7783-0.9166, 0.7609-0.8336 and 0.8384-0.9069 and q2 = 0.7453-0.8924, and 0.7311-0.7939 and 0.8051-0.8843 for sub-training, calibration and test set, respectively. Furthermore, F value and standard error of estimation provided good statistical results for the predictive performance of QSAR models. Interpretations of the derived structure-activity relationship provided pertinent knowledge on the origins of good and poor neuraminidase inhibitory activity. Therefore, the QSAR model holds great potential for the rational design of novel neuraminidase inhibitors.

The antiproliferative activities of new substituted tetrahydroisoquinolines (THIQs) are described. Their cytotoxicities against Ishikawa human endometrial cell line were determined after 72 h drug expose employing Celtiter-Glo assay at concentrations ranging from 0.01 to 100,000 nM. The antiproliferative activities of the compounds understudy were compared to tamoxifen (TAM). In-vitro results indicated that most of the compounds showed better activity than TAM. The most active compounds obtained in this study were 1, 2, 3 and 22 whose IC50 values are 1.41, 0.91, 0.74 and 0.36 μM respectively. This study helped us to evaluate the risk of developing endometrial cancer in the design of nonsteroid estrogen receptor modulators with no agonistic effects on uterus. In-silico pharmacophore hypotheses were generated using GALAHAD and PHASE and the best models with a probable bioactive conformation(s) for these compounds were proposed. These conformations and the alignments of the molecular structures give us an insight in designing compounds with better biological activity.

We consider dialkyl esters of 5-aminosulfonylisophthanoate-based compounds in our efforts to determine factors involved in determining the overall inhibitory activity against estrone sulfatase (ES). We propose that the weak inhibition observed is due to the increased electron density in the area of the phenyl ring close to the sulfamate moiety.

Protein tyrosine phosphatase 1B (PTP1B) is a well known drug target for the treatment of type 2 diabetes mellitus (T2DM). Diverse inhibitors have been reported in literature that inhibit PTP1B. We have reported 2-substituted benzoxazole class of In PTP1B inhibitors earlier. Present work describes 2-substituted benzothiazole compounds as PTP1B inhibitor as an extension of our previous study. Compound 23c, a disubstituted para-Bromobenzyl sulfonamide compound, exhibited moderate biochemical potency (Ki) of 1.4 μM. SAR on synthesized compounds was explained using molecular modeling study.

The present study deals with successful utilization of both correlation and classification techniques for the development of diverse models for the prediction of dual mTOR and PI3Kα inhibitory activities using a dataset comprising of 39 analogues of 4-morpholinopyrrolopyrimidines. Decision tree, random forest, moving average analysis (MAA) and multiple linear regression (MLR) were used to develop models for mTOR and PI3Kα inhibitory activities. The proposed models were also found to be sensitive towards the cell inhibition against PC3. The models were assessed for statistical significance in terms of overall accuracy of prediction, specificity, sensitivity, Mathew’s correlation coefficient (MCC) and intercorrelation analysis. The high predictability of the proposed models of diverse nature offers enormous potential for providing lead molecules for the development of potent medicinal agents for dual mTOR and PI3Kα inhibition.

A series of pyrazole analogues of curcumin were synthesized and investigated for in vitro and in silico antimicrobial activity. The structures of newly synthesized compounds were ascertained on the basis of their analytical and spectral profiles. The compounds were subjected to molecular docking studies for the inhibition of the enzyme glucosamine-6- phosphate synthase [GlcN-6-P]. The autodock program 4.2 was employed to perform automated molecular docking. The docking study was performed on two different active sites of the enzyme reside with the amino acid series Cys1, Arg73, Thr76, His77, Asn98, Gly99, Ile100 and Gly301, Thr302, Ser303, Ser347, Gln348, Ser349, Thr352, Lys485, Ala602, Val605 respectively. Among the thirteen molecules taken for docking studies, compounds cp10, cp11 and cp12 showed minimum docking energy and inhibition constant and may be considered as good inhibitor of GlcN-6-P synthase.

A cost-effective and improved process was developed for the synthesis of the antiviral drug Valacyclovir hydrochloride 1. The process involves the Streglich condensation between 4 and 6 to obtain N-Phthalimide-L-Valine ester 5, which was deprotected by using 40% monomethylamine Overall, the chemistry has been developed and used to prepare Valacyclovir drug 1 in an overall yield of 61 %.

A series of 6-alkoxy-2-(4H-1,2,4-triazol-4-yl)benzothiazoles was synthesized and evaluated for their anticonvulsant activity using the maximal electroshock (MES) method. Interestingly, all of the compounds prepared showed long duration of protection effect in the MES screens. And none of them, except compounds 4b and 4d, showed any neurotoxicity at dose of 300 mg/kg. Compound 4c was considered as the most promising one with an ED50 value of 39.4 mg/kg, and a superior PI value of 17.3 when compared to the marketed antiepileptic drugs carbamazepine, phenobarbital, and valproate. What’s more, compound 4c showed high protection against seizures induced by pentylenetetrazole.

Background: Anesthesiologists can choose from several generic sevoflurane products available. Although both original and generic products contain high-purity sevoflurane, their minor components appear to be subtly different. We previously reported that original sevoflurane products contain a greater amount of water and smaller amount of related substances than generic sevoflurane. Since then, the manufacturer has developed a new type generic sevoflurane product by improving the method of production. The aim of this study was to analyze and compare the compositions of the original, new generic and old generic sevoflurane products. Materials and Methods: Twenty-four bottles of sevoflurane were prepared. In the first two tests, two bottles of each type of sevoflurane were stored in two types of vaporizers for 3 days each. In the third test, the same number of bottles of each sevoflurane type were stored at room temperature (24°C) for 3 days. In the fourth test, the bottles were incubated at a high temperature (40°C) for 3 days. Thereafter, the contents of sevoflurane, water, soluble fluoride and related substances were measured via gas chromatography. Results: Original sevoflurane contained a larger amount of water than the new and old types of sevoflurane. The new sevoflurane had significantly smaller amounts of related substances than the old sevoflurane. When stored in vaporizers for 3 days, the amount of related substances in the original and new type of sevoflurane was in the same range. Conclusions: Our results suggest that the quality of the new and original sevoflurane products is similar under common clinical conditions.

As a part of our ongoing studies in developing new derivatives as dual antibacterial/antifungal agents, we describe the synthesis of novel amino substituted benzofuroxan derivatives. These compounds were tested for their antifungal activity against various strains. It is shown that their antimicrobial and antifungal activities depend on the structure of the amino moiety, on the position and on the nature of the substituents of the benzofuroxan ring. They displayed good bacteriostatic and fungistatic activities comparable to those of reference drugs. The more active benzofuroxan derivatives have been studied intraperitoneally in mice to get a first estimation of their toxicity. Preliminary results have also shown that some derivatives are able to inhibit enzymes such as GDH (glucose dehydrogenase).

Flexible hydroquinone-based compounds were previously proposed as potential mutant-resistant NNRTIs inhibitors, however, experimental or computational evidences did not support this proposal. Herewith, using an integrated in-silico computational approach involving de-novo drug design, structure-based virtual screening (SBVS), molecular dynamics simulations and post-dynamic per-residue binding energy decomposition analysis, the binding affinity as well as the interaction landscape of novel flexible hydroquinone-based compounds were investigated to explore their activity as potential NNRTIs. The proposed leads were found to exhibit improved binding affinity when compared to FDA-approved NNRTIs, rilpvirine, nevirapine and efavirenz, however, the bioavailability profile of these compounds could hamper their uses as effective drugs. Results obtained from this extensive study could assist medicinal and biochemistry researchers with further experimental investigations.