Letters in Drug Design & Discovery - Volume 6, Issue 2, 2009

Peptide mimetic compounds 9d and 9h showed good selectivity for FVIIa/TF over other serine proteases. Xray crystal structure analysis revealed that a large moiety at P3 interacted in a novel manner with the 170-loop and was accompanied by ligand-induced conformational change of the 170-loop. From additional optimization, we discovered compound 10b, an excellent extrinsic pathway-selective inhibitor.

In order to better understand the binding mode of hydroxamic acid derivatives as urease inhibitors, 3D-QSAR and molecular docking studies were conducted on a set of twenty seven urease inhibitors. The 3D-QSAR models demonstrated good ability to predict the activity of studied compounds after performing a leave-one-out (LOO) cross-validation (q2 = 0.848, 0.755) and (r2 = 0.978, 0.984) for the CoMFA and CoMSIA models, respectively. The predictive ability and robustness of the models were validated by a test set compounds and docking simulation.

A series of N-substituted thiazolidinone derivatives 5(a-j) was synthesized in good yield. All the compounds were screened for their in vitro H+, K+- ATPase inhibitory activity. The structures of the synthesized compounds were confirmed by the spectral data. Compounds 5d, 5e, 5f and 5c showed potential H+, K+- ATPase blocking activities, when compared to standard drug Lansoprazole. Structure-activity relationship studies, with various chemical groups, revealed that position and nature of the substitution on the N-thiazolidinones are crucial for H+, K+- ATPase inhibitory activity.

A series of substituted 1H-pyrrol-2(5H)-ones and three 2(5H)-furanones were designed and chemically synthesized. Their inhibitory activities against P. aeruginosa biofilm formation were investigated by using atomic force microscope (AFM) and scanning electron microscope (SEM) technologies. Brominated 1H-pyrrol-2(5H)-ones were found to significantly inhibit P. aeruginosa biofilm formation.

Chemokines receptors have emerged as promising targets for discovery of agents against the HIV/AIDS pandemic. With the purpose of designing new chemical entities with enhanced potencies against the CCR5 chemokine receptor, the QSAR study carried out on 42 novel piperazine derivatives as antagonists of CCR5 HIV co receptor is presented. The developed model was validated by standard QSAR parameters and through a detailed structural investigation on how it reproduces and explains the quantitative differences seen in experimentally known pharmacological data. The model showed a good correlative and predictive ability having a cross validated correlation co-efficient (r2 cv) of 0.768 and a conventional correlation co-efficient (r2) of 0.914. The predictive correlation coefficient (r2 pred) was found to be 0.654. The study revealed that the CCR5 antagonistic activity exhibited by the series is largely explained by steric factors and lipophilicities of substituents and emphasized the role of substituent size and shape in forming effective antagonist-CCR5 binding chemistry. A detailed investigation was made on the structural basis for the antiretroviral activity and the insights gleaned from the study could be usefully employed to design antagonists with a much more enhanced potency and selectivity.

In this study, we have evaluated the stability of poly (D,L-lactide-co-glycolide) (PLGA)-DNA microparticles prepared by using several types of polymers (RG502, RG503, RG504, RG502H, and RG752). Particles were characterised in terms of size, zeta potential, morphology and structural integrity just immediately after preparation, after lyophilisation and after 2 years of storage at -20°C. DNA has been demonstrated to be sufficiently stable for efficient incorporation into PLGA microparticles at least for 2 years after lyophilisation.

A derivative of gossypol, 6,7,6',7'-Tetrahydroxy-5,5'-diisopropyl-3,3'-dimethyl-[2,2'] binaphthalenyl- 1,4,1',4'-tetraone (Apogossypolone, ApoG2), has been synthesized from gossypol acetic acid. Its structure was identified by IR, NMR, MS spectrum and cancer cells in vitro growth inhibition experiments were performed. The results indicate that apogossypolone exerts strong in vitro growth inhibition in human prostate cancer cells, representing a promising cancer therapeutic.

The syntheses and cytotoxic activity of coumarin-estrogen conjugates are described. In vitro results indicated that conjugates 10, 11 and 13 show growth inhibitory activities at 5-dose concentration (100, 10, 1, 0.1, 0.01 μM) against the following NCI-7- human breast cancer cell lines: BT-549, HS 578T, MCF 7, MDA-MB-231/ATCC, MDA-MB-435, NCI/ADR-RES, and thus serve as new leads for further development of antibreast cancer agent.

Novel O,O-diethyl 1-benzamido-2,2-biscarbamoylethanephosphonates were synthesised as putative substrates to HIV-1 PR, to exploit the state of activation of the phosphonate electrophilic function in β-carboxamidophosphonate arrangements. O,O-Diethyl 1-benzamido-2,2-bis[(1S)-N-(1-benzyl-2-hydroxyethyl)carbamoyl]ethanephosphonate exhibited moderate anti-HIV activity in vitro (EC50 = 53 μrbamoyl]ethanephosphonate inhibited HIV-1 PR (IC50 = 31 μM).

Novel 1-benzhydryl piperazine derivatives 7(a-k) and 8(a-i) were synthesised in order to determine their antimicrobial activity and possible structure-activity relationships to improve the efficacy. Their chemical structures were confirmed by 1H NMR, IR and elemental analysis. All the compounds were screened for their in vitro antibacterial activity against Bacillus subtilis, Escherichia coli and Staphylococcus aureus by using Streptomycin as positive control and antifungal activity against Aspergillus niger, Cephalosporium acremonium and Fusarium moniliforme by using Nystatin as positive control. Among the synthesized novel compounds 7h, 7k, 8g, 8h and 8i showed potent antimicrobial activities compared to the standard drugs. The SAR studies reveals that, both linkage and substituents on phenyl ring are responsible for the antimicrobial activity for these class of agents.

Present study describes the synthesis and pharmacological characteristics of the 18βH-glycyrrhizic acid complex with nifedipine, molecular composition 1:4. The study showed that complex decreases arterial pressure at the dose of nifedipine 10 times smaller than the therapeutic dose. Antiarrhythmic effect of nifedipine in this complex was obtained at the dosage 29 times lower than that ensuring antihypertensive action.

The effects exerted by a novel α2-adrenoceptor antagonist SL84.0418 on the acute opiate withdrawal induced by morphine (μ and κ opioid receptor agonist), DAMGO (highly selective μ opioid receptor agonist) and U-50488H (highly selective k opioid receptor agonist) was investigated in vitro. Furthermore, a comparative study was performed with yohimbine, a well known α2-adrenoceptor antagonist. Following a 4 min in vitro exposure to the opioid agonist, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone (80% of contraction vs acetylcholine control) whereas per se the addition of SL84.0418 and yohimbine before naloxone did not induce contracture. The addition of SL84.0418 (1x10-6-5x10-6-1x10-5 M) 10 min before each opioid agonist produced a concentrationdependent increase of the opioid withdrawal and its efficacy was comparable to yohimbine (1x10-6-5x10-6-1x10-5 M). The results of our experiments indicate that SL84.0418 is able to influence opiate withdrawal in vitro thus confirming an important functional interaction between the noradrenergic system and opioid withdrawal.

A series of 3-amino- and polyaminosterol analogues of squalamine and trodusquemine were evaluated for their in vitro antimalarial properties against chloroquine-susceptible and -resistant Plasmodium falciparum. These derivatives were designed possessing a good therapeutic index compared to chloroquine with IC50 varying from 2 to 22 μM. These compounds as well as the underlying design rationale may find usefulness in the discovery and development of new antimalarial drugs.