Letters in Drug Design & Discovery - Volume 6, Issue 7, 2009

Alkaloid lappaconitine (I) and its derivatives - N(20)-deethyllappaconitine (II) and 5'-bromolappaconitine (III) in the base form and as salts - hydrochloride (I•HCl), hydrobromide (preparation allapinine) (I•HBr), hydrobromide (II•HBr), hydrobromide (III•HBr), succinate (I•Suc) were taken for research of pharmacology activity. Moreover, pharmacology activity was investigated for a clathrates of lappaconitine - the bases, hydrochloride and hydrobromide with glycyrrhizic acid (IV) (I-IV; I•HCl-IV; I•HBr-IV). It is shown that, neither the base nor the salts, with the exception for hydrobromide, possess antiarrhythmic action on any of the models. Among glycyrrhizic acid clathrates, only the clathrate with hydrobromide of lappaconitine (I•HBr-IV) has a high activity on the two models of arrhythmia.

The synthesis and preliminary biological investigation of three methylene bridged heterocyclic analogues of trifenagrel, a potent inhibitor of arachidonate-induced aggregation of platelets, is reported. The synthesis of the compounds is based on the cyclocondensation reaction of a tricyclic 1,2-diketone with an appropriate aldehyde, hydrazide or a diamine to form an imidazole, a 1,2,4-triazine or a pyrazine moiety respectively. In comparison to trifenagrel, its methylene- bridged analogue had much reduced activity, while its pyrazine analogue was devoid of activity.

Peptide deformylase (PDF) is a ubiquitous bacterial metalloenzyme responsible to cleave the formyl group from nascent polypeptides, supporting in the maturation. It plays a vital role in the survival of bacterial cells which is conserved in the eubacteria and is considered to be an attractive target for developing new antibacterial agents. Homology modeling was employed for generation of 3-D structure of PDF of M. tuberculosis H37Rv and showed 92.5% amino acid in the allowed region of Ramachandran plot. PDF was used as target for a set of inhibitors with substantial structural differences. Docking results show that the BB-3497, BBS-54, Actinonin and BBS-02 bind with high affinity to enzyme active site. Phylogeny of PDF in M. tuberculosis H37Rv shows homology with other strains of pathogenic bacteria. These data validate PDF as a novel target for the design of a new generation of antimycobacterial agents.

The E2 protein from HPV 16 was selected as a molecular target and its known structures were exploited for broad scope of “hits” to be identified in the screening process. We compared both structure-based and ligand-based design approaches for virtual screening. Databases enriched in natural compounds were used for virtual screening based on molecular docking. In this study, we identified novel classes of HPV inhibitors by means of a structure-based drug-design protocol involving Pharmacophore based virtual screening with molecular docking simulation.

To elucidate further our structural activity relation on the chemistry and antimicrobial activity, a series of novel N-alkylated benzotriazole derivatives bearing pharmaceutically important substituted biphenyl and benzyl halides were synthesized. The synthesized compounds were characterized and tested for in vitro antimicrobial activities by MIC determination against a panel of susceptible and resistant Gram-positive and Gram-negative microorganisms. The synthesis has been carried out using microwave irradiation method with solvent and without solvent. The obtained results showed high yields. Interestingly, compounds 2a and 2b showed a two fold increased antibacterial activity than the standard drug tested and the compounds 2d and 2e showed potent antifungal activity than the standard drug tested.

Sixteen hydrazones were synthesized as derivatives of 1H-1-pyrrolylcarbohydrazides. Five products exhibited 68-97% inhibition against Mycobacterium tuberculosis H37Rv at 6.25 μg/mL using MABA, the most active displaying IC50=7.979 μg/mL and IC90>100 μg/mL. Activities correlated with the hydrophobic parameters according to second order QSAR model favoring 4.4 ≥ LogP ≥ 5.2.

We report the synthesis, evaluation and rationalisation of the inhibitory activity of a series of compounds as probes of the active site of the type 3 of 17β-hydroxysteroid dehydrogenase (17β-HSD3). Results have provided invaluable insight into the active site (as well as supporting the previously reported model) of 17β-HSD3.

We report the synthesis and evaluation of a range of 2-, 3- and 4-substituted derivatives of benzyl imidazole as probes of the active site of the enzyme 17α-hydroxylase/17,20-lyase (P45017α). In conclusion, the positioning and nature of the substituent appears to play an important role in the inhibition of this enzyme complex.

Twenty-one α,β-unsaturated ketone analogs of combretastatin-A4 (CA-4) that were designed for good solubility in aqueous media were synthesized. Compounds defined as Type A were derived from phenylacetone, in which subclass I contained ortho-, meta- or no substituents, sub-class II contained para-substituents, and sub-class III consisted of two substituents. Type B compounds were derived from cyclopropyl 2-fluorobenzyl ketone. The cis-configuration of the target compounds was ascertained through a single crystal X-ray crystallographic analysis of the fluorine-containing compound 8f. Five of the analogs, 8c, 8j and 8l of Type A and 9d and 9i of Type B, were shown to display modest cytotoxic potency (IC50 in the 3.8 - 21 μM range) against the growth of murine melanoma (B16) and leukemia (L1210) cells in culture. Compounds 8j, 8l and 9i were further tested against MDA-MB-435 human melanoma cells. The cyclopropanecontaining compound 9i was the most potent; with an IC50 value of 2.4 μM. Even though no appreciable effects on interphase microtubules were observed when A-10 cells were treated with 30 μM 8j or 8l, compound 9i caused extensive microtubule depolymerization at this concentration. These results suggest that compound 9i of Type B has a similar mechanism of action as CA-4 whilst compounds 8j and 8l of Type B are likely to have a different mechanism of action.

A new ethyl 3-(quinazolin-4-ylamino)-1H-pyrrole-2-carboxylate derivative has been designed and synthesized as antitumor agent, which was identified by 1HNMR, 13CNMR, IR, MS and EA. The antitumor activity of the new compound was tested against human pancreatic cancer Miacapa2, pancreatic cancer Panc1, prostate cancer DU145 and prostate cancer PC3 cells in vitro, and the target compound crystal structure has been characterized by x-ray crystal analysis.

A series of lactyl cholesterols as targeting liposome ligands for brain-specific delivery were synthesized. The lactic acid protected by benzyl group was coupled with cholesteryl oligoethylene carboxylate derivatives 3, then deprotected in tetrahydrofuran by Pd/C with H2 to obtain the title compounds La-Lf. As a model drug, tegafur was entrapped by liposmes and lipsomes coated with these ligands for in vivo study, which showed that the ligand could enhance the ability of liposome delivering tegafur across the blood-brain barrier.

A series of novel 2,3,4,5-tetrahydro-7-alkoxy-1H-2-benzazepin-1-ones derivatives was synthesized and screened for its anticonvulsant activities by the maximal electroshock (MES) test and its neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The MES is the most commonly used method of screening antiepileptic drugs. 2,3,4,5-tetrahydro-7-heptyloxy-1H-2-benzazepin-1-one 4e, revealed as the best anticonvulsant activity, exhibited median effective dose (ED50) of 39.4 mg/kg, and median toxicity dose (TD50) of 392.9 mg/kg, resulting in a protective index (PI) of 10.0, which is a little higher than the PI of the marked antiepileptic drug carbamazepine (PI=6.4). Comound 4e also underwent further anticonvulsant tests evaluating its activity in some chemically induced seizure models, including pentylenetetrazole (PTZ), isoniazid, 3-mercaptopropionic acid (3-MP), and thiosemicarbazide.