Letters in Drug Design & Discovery - Volume 10, Issue 1, 2013

In this study, a combined in vitro antifungal and enzymatic studies with molecular modeling techniques are presented. Although attempts with rational design strategies have been made, the bioactivity of studied 1-substituted 4- ethoxycarbonylmethylthiosemicarbazides 1a-1g was only marginal. Among the compounds tested, antifungal response was observed only for indole derivative 1f and pyrazine derivative 1g. The most important results of the antifungal screening assay can be summarized as follows: (i) the replacement of an aryl ring in 4-arylthiosemicarbazides with a flexible chain reduces antifungal response dramatically, (ii) NH-NH-C(=S)-NH core seems to be important for antifungal activity of thiosemicarbazides. Based on docking simulations fungal secreted aspartic proteinase (SAP) was proposed as the putative enzyme target for thiosemicarbazide derivatives with a flexible chain at the N4 position of thiosemicarbazide core.

Autotaxin (ATX or NPP2) is a newly discovered secreted glycoprotein lyso-phospholipase D (lysoPLD). Its main role is the lysoPLD activity, which transforms lyso-phosphatidylcholine (LPC) into lyso-phosphatidic acid (LPA). ATX contributes to tumor progression, inflammation, obesity and diabetes and constitutes a target for drug design. Various synthetic phospholipid analogues have been explored as ATX inhibitors. However, potent and selective non-lipid inhibitors of ATX are currently not available. Some new ATX inhibitors have been subjected to a Quantitative-Structure Activity Relationships (QSAR) analysis. CMR represents the calculated molar refractivity of the molecules and seems to govern the ATX inhibition. Steric factors are obviously important. No role for lipophilicity was found. Electronic parameters are not found to be present.

The aim of this study is to design and synthesize novel dual inhibitors of Src protein tyrosine kinase (PTK) and Glutathione S-transferases (GSTs), as a potential drug lead with therapeutic efficacy on cancer and immune disorders. The biological activity profiling of small molecule inhibitors via miniaturized biochemical techniques compatible with medium throughput screening and focused screening methodologies were performed. To determining the effects of small molecule inhibitors on Src kinase and Phase II detoxification enzyme GST isozymes in liver homogenates used to verify their roles in drug resistance mechanism for cancer chemotherapeutics. In this study, 14 indole-3-imine-2-on and N-benzyl indole-3-imine-2-on derivatives were synthesized for dual activities against Src and GST. The chemical structures and purities of compounds were verified by IR, 1H NMR, MASS spectroscopy, and elemental analysis. The compounds 2, 3 and 9 are found slightly active against both enzyme Src and GST.

A series of novel 1,2,4-triazole derivatives has been designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells. Three of them showed moderate activities against wild-type HIV-1 with an EC50 ranging from 17.4 μM to 4.87 μM. Among the active compounds, 3-((4-(3,4-dimethoxybenzylideneamino)- 5-(furan-2-yl)-4H-1,2,4-triazol-3-ylthio)methyl)benzonitrile (4d) was identified as the promising compound (EC50 = 17.4 μM, SI =13). However, no compound displayed inhibitory activity against HIV-2.

A new series of N-(4-chlor-2-methylphenoxy)ethyl- (1-6) and N-(4-chlor-2-methylphenoxy)acetylaminoalkanols (7-10) has been synthesized for evaluation of their anticonvulsant activity. Pharmacological tests included maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure (ScMet) assays, as well as rotarod for neurotoxicity (TOX) and were performed in mice i.p. and rats p.o. The activity of the compounds in the group was various, and the most active compound in mice was R,S-1N-[(4-chlor-2-methylphenoxy)ethyl]aminopropan-2-ol, revealing 100% activity in MES test at 30 mg/kg b.w., 0.5 h after administration without toxicity at the same dose and time. In rats (p.o.), the most active compound was 2N-[(4-chlor-2-methylphenoxy)ethyl]amino-2-methylpropan-1-ol, revealing 25% activity in MES at 30 mg/kg b.w. 0.5 and 1 h after administration.

In the present study, N-(benzhydryl/thiazol-2-yl)-2-(piperidin-1-yl)acetamide derivatives were obtained by the reaction of 2-chloro-N-(benzhydryl/thiazole-2-yl)acetamides with piperidine derivatives. The chemical structures of the compounds were elucidated by IR, 1H-NMR, and mass spectral data and elemental analyses. These compounds were investigated for their antimicrobial effects. The microbiological results revealed that the compounds were more effective against C. albicans (ATCC-22019) than bacteria. Among all compounds (1-9), compound 3 bearing benzhydryl and 4- methylpiperidin-1-yl moieties was found to be the most effective compound against C. albicans. Compound 3 exhibited antibacterial activity against P. aeruginosa with a MIC value of 62.5 μg/mL, whereas streptomycin showed antibacterial activity against P. aeruginosa with a MIC value of 125 μg/mL. Furthermore, compound 3 exhibited the same level of antibacterial activity against S. aureus when compared with streptomycin. Other derivatives did not show significant activity against the tested bacteria.

Metalloprotein is a basic term for a proteins that contains a metal ion cofactor, have many functions in cells, such as enzymes, transport and storage proteins, and signal transduction proteins. The balance between MMPs and TIMPs are critical in extracellular matrix (ECM) development, morphogenesis, tissue repair and remodeling through MAPK Pathway. Excess of MMPs and TIMPs shows adverse effects, leading to aging diseases such as Alzheimer's Disease, Cancer, Asthma, Diabetes 2 Mellitus etc. Human Protein Reference Dataset (HPRD) assessed 10 interactions for TIMP1, 5 interactions for TIMP2, 8 interactions for TIMP3 and 2 interactions for TIMP4. The data also assessed 11 interactions for MMP1 and 11 interactions for MMP2. The data from HPRD and Pathwaylinker has also predicted the interaction of Metalloproteins with aging diseases. In the present experimentation, in silico docking models predicted that Iron and Cobalt are activators for TIMPs and MMPs. These metals can serve as an important reactants with good binding affinity for TIMPs and MMPs. Except TIMP1 and TIMP2, all other TIMPs used in present experimentation have good binding affinities with Cyanocobalamin. Hence Cyanocobalamine can be used in treatment of various diseases such as D2M, Cancer, Alzheimer and Parkinson diseases in low dose for longer period, in control of MAPK pathway.

To overcome solubility problem observed in early preclinical study with the potent multidrug resistance reversing agent HZ08 which containing tetrahydroisoquinoline skeleton, we synthesized a series of HZ08 analogues with improved soluble properties. Compounds 6f, 10c and 10f showed significant reversal activity with little cytotoxicity. The median inhibitory concentration (IC50) values of adriamycin were reduced to 0.9 μM, 1.1 μM and 0.71 μM, respectively and comparable to those of reference drug verapamil (1.1 μM) and lead compound HZ08 (0.8 μM) on K562/A02 cells. The solubility of all newly synthesized compounds had been improved.

A novel series of hybrids of indolin-2-one and quinazolin-4(3H)-one linked via an imine bond were synthesized and tested for their inhibitory activity against the proliferation of a panel of five human cancer cell lines. We found that compound 5c bearing 5-bromo substituent at the indolin-2-one ring exhibited weak cytotoxic activity with percentages of inhibition ranging from 27% to 49% at 20 μM, while its counterpart 7c having 4-methoxybenzyl group at the N1-position of indolin-2-one ring was more active with percentages of inhibition in range of 32-63%. These results indicate that the presence of a bromo substituent at the 5-position and a 4-methoxybenzyl group at the N1-position of indolin-2-one ring is important for the cytotoxic activity.

Tubulin has received more attention as potent anticancer drug target because it is the fundamental unit of microtubules and plays an active role in cell division. The drugs against β-tubulin are mainly derived from terrestrial plants and marine resources. Of these, red and brown algae from the marine environment produce better secondary metabolites. These compounds are found to be active against cancer cell lines. Since there is no study reported till date about the activity of these compounds against human β-tubulin, we have investigated the role of 517 compounds available in the seaweed secondary metabolites database against modeled human β-tubulin. All the conformers of lead compounds (RL381, RL366, RL376 and RG012) when docked at the taxol binding site showed better interactions with the H1-S2 loop and M-loop which are actively involved in lateral interactions of tubulins and also with the helix H7 which is the connecting link between N-terminal and intermediate domain. Important residues involved in polar interaction by these lead compounds were D224, H227, R276, R282 and R359 which closely mimicked the interaction of taxol with β-tubulin. We then attempted to calibrate the available molecules based on their Lipinski rule, binding affinity and other descriptor based comparison to identify potential lead molecules which could be used as drugs against human β tubulin.

A novel series of 2-piperidinyl quinoline chalcones/amines (3-21) as structural analogues of quipazine were designed in order to find a promising candidate having antidepressant potential. They were synthesized, characterized and screened in vivo for their antidepressant potential by two behavioural models viz. forced swim test (FST) and learned helplessness test (LST). FST showed that compound 5, 8 and 17 reduced significantly the duration of immobility at 20 mg/kg, when compared with the control (p<0.001), and demonstrated comparable activity to clomipramine (p<0.001). LST further supported the antidepressant potential of these compounds. Furthermore, in 5-HTP-induced head-twitch test and yohimbine-induced mortality test, most active compound 5 increased the rate of head-twitching and the prevalence of mortality. Thus, the mechanism of action of the antidepressant effects of compound 1-(2,4-Dichlorophenyl)-3-[2- (piperidin-1-yl) quinolin-3-yl] prop-2-en-1-one (5) may be attributed to increased 5HT and NE level in the synapse.

Synthesis of novel N-substituted β-hydroxy amines 4(a-j) and β-hydroxyethers 5(a-c) with chiral benzoxazine fluoroquinolones has been described. Benzoxazinefluoroquinolone carboxylic acid 1, on reaction with piperizine in acetonitrile in presence of triethylamine under reflux gives 7- piperazinyl benzoxazine fluoroquinolone 2. The latter is reacted with epichlrohydrine in presence of NaOH in acetone to yield respective N-substituted epoxide 3 with retained chirality, the 3 on treatment with different amines gives respective β-hydroxy amines 4(a-j). On other hand, 3 on treatment with alcohols in presence of NaOH afforded the corresponding β-hydroxy ethers 5(a-c). The structures of the synthesized compounds have been established on the basis of its spectral and analytical data. The antimicrobial activity of newly synthesized compounds ware evaluated against different microorganisms comparing with levofloxacin and found all the compounds exhibited remarkable activity.