Letters in Drug Design & Discovery - Volume 8, Issue 5, 2011

Ten new RGD (Arginine-Glycine-Aspartic acid) peptidomimetics have been synthesized and screened for their affinity to αvβ3 integrin receptor. Arginine and Aspartic acid mimetic subunits were connected through 1,2,3-triazole as central scaffold by click chemistry, affording the final products with good yields. Among them, compounds 3f-j exhibited high affinity to the receptor,with IC50 in the low nanomolar range, comparable to that of the reference compound Cilengitide.

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyzes the oxidation of the potent estradiol (E2) to the less active estrogen estrone (E1). Inhibitors of this enzyme should maintain the local level of E2 in bone tissue when the E2 concentration in the circulation drops and therefore might be useful for the treatment of osteoporosis. In this work, novel non-steroidal spiro-δ-lactone compounds designed as 17β-HSD2 inhibitors were synthesized and their physicochemical and biological properties were investigated. These new spiro-δ-lactones are not sufficiently stable for further development and show low inhibition of the enzyme.

A series of indoledione derivatives displaying potent activities against ELOVL6 were selected to establish three-dimensional quantitative structure-activity relationships (3D-QSAR) using CoMFA and CoMSIA methods. A training set of 30 active compounds was used to develop the models while a test set of 8 compounds was used for the external validation. The CoMFA analysis predicted a q2 value of 0.817 and an r2 value of 0.990. The best CoMSIA model, based on a combination of steric, electrostatic and hydrophobic effects, predicted a q2 value of 0.760 and an r2 value of 0.959. These models were graphically interpreted using CoMFA and CoMSIA contour plots which provided insight into the structural requirements for increasing the activity of a compound. The results obtained from this study provide a solid basis for future rational design of more active ELOVL6 inhibitors.

Molecular modeling (MM) study is performed for Pipecolic acid based derivatives (PSAs) of tumor necrosis factor-α converting enzyme (TACE) inhibitors because of their very high selectivity for TACE over MMP-1. MM study was carried out by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular field Similarity Indices Analysis (CoMSIA) approaches. Computational docking simulations have also been performed to explore atomic details of TACE/PSA interactions and to identify the most important structural features of PSAs vital for TACE inhibitory activity. Molecular modeling study was performed using probable bioactive conformations, generated employing docking, for molecular alignment. The CoMSIA model resulted to be more predictive than CoMFA model, and gave conventional r2 0.996, r2cv 0.765, q2 0.783, SEE 0.025, F-value 472.149, r2boot 0.999 and r2test 0.788. Generated 3D-QSAR field contributions (contour maps) and results of docking analysis showed good correlation. Therefore, present studies will be useful for designing new molecules with improved TACE inhibitory activity in future.

Andrographolide derivatives have been reported as potential α-glucosidase inhibitors. A more detailed investigation of active sites and key residues of α-glucosidase, which can interact with andrographolide derivatives, is useful for the discovery of more effective α-glucosidase inhibitors. To establish a virtual method predicting potential active sites and key residues, a 3D structure of α-glucosidase from baker's yeast was first constructed by homology modeling (RMSD of alignment was 1.745Å). The SiteID program was then used to explore the potential binding sites of the homology model of α-glucosidase. Based on these potential binding sites, 25 andrographolide derivatives were docked into the homology model of α-glucosidase for determining the potential active sites. Results showed that the predicted strong inhibitors' AR (accuracy rate) of the two potential active sites, P7 and P10, were 77.8% and 88.9% respectively. To further research the potential active sites, key residues of these predicted active sites were investigated through the virtual residues knockout method. VAL316 and THR307, residues of P7, and HIS258, LYS262, ILE271, MET272, THR273, ALA289, TYR292, and SER295, as well as residues of P10, were found to contribute greatly to the high ARs of their corresponding active sites. These results may be useful for design of new α-glucosidase inhibitors.

A series of N4-aryl substituted isatin-3-thiosemicarbazones was prepared by the reaction of isatin with an appropriate thiosemicarbazide in ethanol containing a few drops of acetic acid. The newly synthesized compounds were characterized by means of their analytical (CHN) and spectral (IR, 1H-NMR, EIMS) data, and evaluated for their cytotoxicity and phytotoxicity potential. Eleven out of thirteen compounds tested proved to be active in the brine-shrimp lethality bioassay exhibiting significant cytotoxic activity with LD50 values ranging from 1.75x10-5M to 1.91x10-4M. In phytotoxicity assay, all the synthesized compounds, regardless of the nature of aryl substituents, demonstrated weak to moderate (5-30%) plant growth inhibition at the highest tested concentration (500 μg/mL).

A series of novel 2-(benzo[d]thiazol-2-yl)-1-(3-methyl-5-substituted-phenyl-4,5-dihydropyrazol-1-yl)ethanone derivatives were synthesized and characterized by NMR, ESI-MS. Biological activity tests results show that compounds 4a, 4b, 4d and 4g displayed activity with MIC of 1.562 μg/mL against B. subtilis ATCC 6633, compound 4d displayed significant activity with MIC of 1.562 μg/mL against S. aureus ATCC 6538. Compound 4a with potent antibacterial activities strongly inhibited S. aureus DNA gyrase and B. subtilis DNA gyrase with IC50s of 0.5 μg/ml against S. aureus DNA gyrase and B. subtilis DNA gyrase.

The compounds 8-butyl(2),8-hexyl-(3),8-octyl-(4),8-decyl(5),8-dodecyl(6) and 8-hexadecyl(7) palmatine derivatives were synthesized and confirmed by UV, IR, CHN, 1H NMR, 13C NMR and MS spectra data. The series of the synthesized compounds has been tested for their antimicrobial activity in vitro to evaluate structure-activity relationships. Substitution of the H with alkyl groups at C-8-H led to significant changes in the antimicrobial activity. The antimicrobial activity of the substituted derivatives was up to 64 times higher than that of palmatine, especially against Gram-positive bacteria. Which increased as the aliphatic chain was elongated and then decreased gradually when the alkyl chain exceeded eight carbon atoms. 8-Octylpalmatin-e (4) displayed the highest antimicrobial activity of all compounds. The LD50 values of compounds (2-7) decreased as the aliphatic chain was elongated. Compound 7 showed the lowest toxicity.

Traditionally, the process of drug development has revolved around a screening approach and trial-and-error method, as no body knew which compound or approach could serve as a drug or therapy. This discovery process was very time consuming and laborious and discovery of a new drug used to take around 8-14 years and costs about US $1.8 billion. In order to minimize the time and cost in this drug discovery process, scientists around the world contributed tremendously and come up with a modern drug-designing program. The beauty of this modern drug designing is that now we can tailor the drug with desired combinations computationally before going for experimental laboratory work. In this review, traditional to modern methods of drug designing & discovery have been discussed. It covers the available web tools/databases and in silico techniques used in virtual screening and drug discovery processes to reduce the wet lab economy and time. Studies suggest that the best method for molecular docking based target identification is probably a hybrid of various types of algorithm encompassing novel search and scoring strategies e.g., PMF score, Dock score, Gold score etc. However, apart from in vitro assays and in vivo experiments, application of in silico QSAR & ADMET in the prediction of biological activity & bioavailability are proving beneficial in drug discovery process.

The paper describes the synthesis and antileishmanial activity of N-substituted imines, obtained from the reactions of primary amines with three biologically important aldehydes/ketones, thiophene-2-carbaldehyde, 2- hydroxybenzaldehyde (salicylaldehyde) and indoline-2,3-dione. Of the fourteen compounds screened from three classes, five compounds showed significant antileishmanial activity. Among the three classes of imines, the class of N-(2- thienylidene)amines showed much better activity than the other two classes. N-(2-Thienylidene)benzhydrylamine showed IC50 value of 0.51 μg/ml. The effect of substituents on the bioactivity is discussed.