Letters in Drug Design & Discovery - Volume 7, Issue 9, 2010

Cyclin-dependent kinases have essential role in the regulation of the cell division cycle. The structure-activity relationship of 4-cyclohexylmethoxypyrimidines, inhibitors of CDK2 as antitumor agents was explored. Since some of the studied 4-cyclohexylmethoxypyrimidines were reported to be among the most potent and selective CDK2 inhibitors reported to date, it was of interest to study QSAR. Useful QSAR equations were generated using dielectric energy (DE), N_Count, indicator parameter, Shadow_XYfrac and Jurs_RASA to consider quantitatively the effect of the structural variation of 4-cyclohexylmethoxypyrimidines on the inhibition of CDK2. The statistical measures such as r, r2, q2, and F values obtained for the training set were in acceptable range and hence this relationship was used and the equations were validated using a test set. The models obtained showed not only statistical significance but also predictive ability and highlights the active compounds' spatial pose in the CDK2 inhibition and that minor values for DE combined with an NO substituent lead to an increasing of CDK2 inhibitory activity. The models obtained might be able to be used predictively to guide design of additional potential CDK2 inhibitors.

Two series of 17 tetrahydroquinoline compounds (2,4-DAr-THQs and DSQs), in which the 4-methoxy-3- hydroxyphenyl (isovanillin) structural unit is incorporated, were tested for their potential human tumor cell growth inhibitory effect on MCF-7, SKBR-3, PC3, HeLa and for non-tumor cells (primary culture of human dermis fibroblast - control cells) for the first time. The THQ 8 is an interesting model for antitumoral drugs, displaying cytotoxic activity against MCF7, SKBR3 or PC3 (IC50 7.99 - 16.14 μM) with the selectivity index 3.4 for MCF7.

A series of novel coumarin derivatives containing 4,5-dihydropyrazole moiety as potential telomerase inhibitors were synthesized. The bioassay tests showed that compound 3b exhibited potentially high activity against human gastric cancer cell SGC-7901 with IC50 value was 2.98±0.16. Docking simulation was performed to position compound 3b into the telomerase (3DU6) active site to determine the probable binding model. The result shows that some coumarin containing 4,5-dihydropyrazole moiety can combine well with the telomerase active site and may have use as potential telomerase inhibitors.

The emphasis of this work was to design and synthetize a new class of bifunctional DNA intercalators, containing in the same molecule an alkylating part and a nitrogen heterocycles intercalator unit. The adopted strategy is general, straightforward, and only involves two steps: acylation and quaternization. An alternative, fast, general, and environmentally friendly method for preparation of these compounds under microwave (MW) irradiation is also presented. The structure of compounds was proven by elemental (C, H, N) and spectral analysis (IR, 1H NMR, 13C NMR, COSY, HMQC, HMBC). The obtained compounds proved to have excellent anticancer activity in vitro. Possible mechanisms of action and structure-activity relationships are discussed.

We report the use of estrone (E1)-based compounds in the search for inhibitors of 17β-hydroxysteroid dehydrogenase, in particular, type 3 (17β-HSD3). Results suggest that the compounds are good inhibitors of 17β-HSD3 and a number were found to be equipotent to the standard inhibitors used within the current study.

The antioxidant capacity of 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles was evaluated. The values of antioxidant capacities of compounds 2d and 2e were found to be, respectively, 2,700 ± 150 and 3,135 ± 230 TE by the ORAC method, corresponding to a significant antioxidant capacity.

A series of cinnamylpiperazine derivatives was synthesized using different benzophenone as starting material. The structures of the compounds were proved by their IR, 1H-NMR spectroscopic data and mass spectra data. The anticonvulsant activities of these compounds were evaluated with maximal electroshock (MES) test and rotarod test with intraperitoneal injection on KunMing mice. Among all the flunarizine analogues, no one exhibited better anticonvulsant activity than flunarizine. Flunarizine (4i) exhibited anticonvulsant activity with ED50 of 38.1 mg/kg, TD50 of 164.3 mg/kg and PI of 4.3 through administration intraperitoneal, and with ED50 of 56.8 mg/kg, TD50 of 456.3 mg/kg and PI of 8.0 through oral administration.

A series of new cyclodextrin linked coumarins was synthesized (12a-g) and evaluated for th ei r antimicrobial activity. All the compounds investigated have shown significant antimicrobial a c t iv i ty against gram-positive and gramnegative bacterial strains as well as a few fungal strains. The compounds exhibited upto 4-fold improved biological activity than their precursors. The results suggest that the improvement in bioavailability is responsible for the enhanced biological activity.

In a previous study, 5-(1-adamantylthio)-3-picoline (I) and 3-(1-adamantylthio)-4-phenylpyridine (II) were shown to have potent antimicrobial activity. The present investigation is concerned with the antimicrobial action of thiopyridines I and II against methicillin-resistant Staphylococcus aureus (MRSA) isolates and with their murine fibroblast (L929) cytotoxicity. Thiopyridine II was found to display significant antimicrobial activity against all of the MRSA isolates tested, with minimum inhibitory concentrations (MIC) of 1-8 μg/mL. Moreover, both I and II attenuate the viability of L929 cells in a dose-dependent manner, displaying an IC50 of 68.4±6.0 and 47.3±5.6 μg/mL, respectively. These findings suggest that thiopyridine II is promising as a lead compound for further development as a therapeutic.

The present paper reports the synthesis and antiprotozoal activity of N-quinolin-8-yl-arylsulfonamides and their copper and zinc complexes. Sulfonamides 2-5 were synthesized by reacting 8-aminoquinoline with several commercial arylsulfonyl chlorides. The corresponding complexes 6-13 were obtained using copper (II) acetate or zinc chloride in methanol. In vitro activity was carried out against promastigote forms of Leishmania braziliensis and L. chagasi, and epimastigote forms of Trypanosoma cruzi. Selected compounds were tested against axenic amastigote forms of L. braziliensis. The new 2,5-dichlorobenzenesulfonamide ligand was found to be inactive under the selected bioassays, however its copper complex 8 was active with the highest selective indexes (SI) against L. braziliensis promastigote and amastigote forms, with IC50 values of 2.59 and 0.35 μM, respectively. Difluorinated copper 10 and zinc 11 complexes were most active against L. braziliensis, with IC50 of 1.11 μM and 1.25 μM, respectively. However, the SI values were about 12 for both compounds. In general, the complexation of sulfonamides increases the antiprotozoal activity, as well as the cytotoxicity on Vero cells. These results confirm the antiprotozoal potential of sulfonamides and metal-based sulfonamides.

Isosteviol is a beyerane tetracyclic diterpenoid with a large variety of biological activities. In this article, a series of novel isosteviol derivatives containing the modification of C-18 carboxyl group (5-12), C-16 carbonyl group (14- 16) and heteroatom-containing frameworks fused with isosteviol structure (18-19) were synthesized and evaluated for their in vivo acute antihyperglycemeric effects. Among them, compound 8 exhibited the most potent antihyperglycemeric effects. Furthermore, primarily, structure-activity relationship (SAR) was also analyzed. The structures of all the newly synthesized compounds were determined by 1H, 13CNMR, MS, IR and elementary analysis.

This study emphasized on the recent developments in the field of anticonvulsant agents. The review illustrates various structural classes of compounds which were evaluated for anticonvulsant action according to the established procedure by the Antiepileptic Drug Development Program of the Epilepsy Branch, National Institute of Neurological Disorders and Stroke, National Institute of Health, USA. This review encompasses some new anticonvulsant agents of various chemical structures, and for most of the compounds the precise mechanism of action is still not known. These newer agents include: tryptamines and isotryptamines, sulfonamides (carbonic anhydrase inhibitors), derivatives of amino acids, isoindolinedione derivatives, lactams and amides, quinazolin-4-(3H)-one derivatives, γ-hydroxybutyric acid (GHB) and its derivatives, semicarbazones and thiosemicarbazones. These new compounds of different structural classes could be handy for designing the future targets and in the determination of their precise mechanism of action. Nevertheless, few new drugs have brought significant advancement in the tolerability of anticonvulsant therapies. This study would be useful to design novel, effective anticonvulsant to combat epilepsy in its numerous forms, with more selective activity and least toxicity.

The development and synthesis of Protease Inhibitors in a Brazilian group led by Professor O. A. C. Antunes is reviewed focusing on the strategies, molecular modeling studies, synthesis and pharmacological evaluation.