Letters in Drug Design & Discovery - Volume 12, Issue 8, 2015

The diagnosis of parkinsonism is essentially made by the presence of typical features including bradykinesia, plastic rigidity and resting tremor. However, in older persons, where the prevalence of parkinsonism is higher, the diagnosis is often inaccurate. The utilization of new radiological techniques, such as the DaT-SCAN SPECT, can improve the early diagnosis and treatment of these patients. However, no data are available at this moment in older population. Aims of this study were to investigate the role of the DaT-SCAN SPECT in the diagnosis of parkinsonism in older persons, and to propose a new diagnostic algorithm on DaT-SCAN SPECT to be used in older persons with parkinsonism. Patients evaluated at the Nuclear Medicine Unit of the University Hospital of Parma for diagnosis of parkinsonism from January 2009 to June 2012 who underwent clinical evaluation, and radiological assessment with DaT-SCAN SPECT, brain CT and MRI. A total of 267 patients, 147 men (55.06%) and 120 women(44.94%) with a mean age of 73.12 ± 5.08 years were enrolled in the study. In the multivariate linear regression analysis including age, sex, and bradykinesia, the presence of cerebral vascular lesions in the CT or MRI was the most significant predictive factor of abnormal DaT-SCAN SPECT uptake (beta± SE, p=0.002). The presence of bradykinesia remained also significantly associated with the DaT- SCAN SPECT uptake. In older subjects, the CT or MRI detection of cerebral vascular lesions and the presence of bradykinesia are the most significant predictors of abnormal DaT-SCANTM SPECT uptake. The timing of scan execution and the coexistence of motor and cognitive deficits, are key elements to improve the accuracy of early detection of altered nigrostriatal system, for avoiding misdiagnosis and side-effects of medications inappropriately started in older persons. This study could facilitate clinicians to treat older persons with Parkinson's disease and to ameliorate the accuracy of the diagnosis for testing the effects of new drugs affecting the natural history of this neurodegenerative disease. The accuracy of the diagnosis could permit an early identification of these diseases, and could permit to test neuroprotective drugs in early phase of patients with Parkinson's disease.

Inositol is a cyclic polyol naturally occurring as seven optically inactive stereoisomers and one enantiomeric pair. Within the human body, brain is the most saturated organ of inositol, mainly with myo- and scyllo-inositol. One of the molecular mechanisms for the maintenance of inositol brain levels is active transport via stereospecific carrier molecules – one hydrogen myo-inositol transporter (HMIT) and two sodium myo-inositol transporters (SMIT1 and SMIT2). In this study, we modeled by homology the myo-inositol transporter SMIT1 using the X-ray structure of Vibrio parahaemolyticus sodium/galactose symporter (vSGLT) as a template. A set of inositol derivatives – strong and weak competitors of inositol transport – was docked in the SMIT1 binding site. The docking protocol was optimized in terms of scoring function, radius of the binding site and flexible residues inside to distinguish between strong and weak competitors. The analysis of ligand – transporter interactions revealed that tiny structural differences exist between strong and weak competitors. Both groups have almost equal number of hydroxyl groups but the strong competitors are able to form more hydrogen bonds with the transporter (5.07 vs. 4.53 per molecule) and take part in less hydrophobic interactions (0.6 vs. 0.73) than the weak competitors.

Detecting early-stage ovarian cancer, the fourth leading cause of cancerrelated deaths in women, is difficult, and the development of novel chemotherapeutic agents is required. Since several flavonoids show anticancer activities against ovarian cancer, 35 naphthylated flavonoids including 3’,4’-naphthochalcones, 5’,6’-naphthochalcone, 7,8-nap-hthoflavones, 5,6-naphthoflavanones, 5,6-naphthoflavones, 2,3-naphthochalcone, N-phenylpyrazolyl-5’,6’-naphthocha-lcones, carbothioamidepyrazolyl-5’,6’-naphthochalcones, pyrazolyl-3’,4’-naphthochalcone, and carbothioamidepyrazolyl-3’,4’-naphthochalcone were designed and synthesized. To explore the anticancer effects of these compounds, clonogenic long-term survival assays were applied on human cisplatin-resistant A2780/Cis ovarian cancer cells. Relationships between the structural properties of 35 naphthylated flavonoids and their clonogenicities were explored using comparative molecular field analysis and hologram quantitative structure– activity relationships. As a result, several structural features that increased cell growth inhibitory activity were identified, and a compound satisfying these conditions, 5-(2,3-dimethoxyphenyl)-3-(1-hydroxynaphthalen-2-yl)-N-phenyl-4,5-dihydro-1Hpyrazole- 1-carbothioamide, was designed and synthesized. This novel compound´s half-maximal cell growth inhibitory concentration was lower than those of the 35 flavonoid derivatives tested here. Therefore, the structural features observed in this report can be used to design and develop potent chemotherapeutic agents to treat ovarian cancer cells.

A new complex [Cu(D-glu)(phen)(H2O)]·NO3·2H2O 1 (D-glu = D-glutamic acid, phen = 1,10-phenanthroline) was synthesized and identified by IR spectroscopy and single-crystal X-ray diffraction. Fluorescence studies showed that 1 exhibited stronger intercalative interaction to CT-DNA as compared to known complex [Cu(L-glu)(phen)(H2O)]·NO3·2H2O 2. Both complexes inhibited the growth of MCF-7 cells with the IC50 values of 0.141 μmol·L-1 and 0.126 μmol·L-1 for complex 1 and 2, respectively. The complexes were 20 times more active than the amino acid - free complex [Cu(phen)(H2O)2(NO33)] · NO3 3.

Mannich bases (2-6) of curcumin analogue 1, [1,5-bis(4-hydroxy-phenyl)penta-1,4-dien-3- one], were synthesized.Their cytotoxicity against human HL-60 promyelocytic leukemia and HSC-2, HSC-3, and HSC-4 oral squamous carcinoma cell lines, as well as against normal oral cells was evaluated. Mannich bases 2-5 displayed more potent cytotoxicity than curcumin and curcumin analogue 1 towards malignant cells with high PSE values (93.7-136.6). PARP1 cleavage assay demonstrated the induction of apoptosis of HSC-2 cells by the most potent and tumor selective compound 4, which is a bis Mannich base having N-methyl piperazine moieties. The results obtained suggest that preparation of Mannich bases of a curcumin analogue 1 was a useful chemical modification for cytotoxicity and tumour-selectivity for the compounds synthesized, and apoptosis can be one of the possible mechanisms of action for the cytotoxicity.

A novel series of 1,2,4-triazole clubbed (E)-5-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(2- hydroxyphenyl)pent-4-ene-1,3-dione (4a-h) and 2-(4-(1H-1,2,4-triazol-1-yl)styryl)-4H-chromen-4- one (5a-h) derivatives have been synthesized by ultrasound and conventional synthetic approach. All the synthesized compounds were screened for antibacterial and antifungal activities. From the series compound 4e and 5a show excellent activity against all tested strain. Compound 5a and 5c shows excellent activity against C. albicans. Molecular docking studies were used to rationalize binding interaction at the active site of fungal enzyme P450 cytochrome lanosterol 14 α-demethylase and results showed good binding interaction. ADMET predictions were performed and it was observed that compounds have good pharmacokinetics and drug like properties.

34 novel ATR inhibitors were used to build an optimal 3D-QSAR model. Homology modeling and molecular docking were used to study the interaction of ATR kinase protein and inhibitor. The results showed that both the CoMFA model (q2 = 0.550; r2 = 0.978; standard error of estimate [SEE] = 0.129; F = 177.729 and r2pred = 0.530) and the CoMSIA model (q2 = 0.632; r2 = 0.991; standard error of estimate [SEE] = 0.088; F = 277.224 and r2 pred = 0.322) are acceptable. The 3D-model of ATR kinase was further assessed by ERRAT, WHATCHECK and PROCHECK, which showed that the final model is reliable with 78.9% of the residues in the most favored regions. According to molecular docking, Ala562, Ser563, Leu564 and Lys585 were the vital amino acid residues to the ATR kinase. This article can support useful information for designing novel and high bioactive ATR kinase inhibitors.

Malaria parasite Plasmodium falciparum actively invades its host cells utilizing its actin/ myosin-based motor machinery. Actin-profilin interaction is essential for actin filament dynamics in eukaryotic cells. P.falciparum profilin (PfPRF) is highly divergent from other eukaryotic profilins and possesses unique structural properties. In this study, we attempted to identify region(s) of P.falciparum actins (PfACT1 and PfACT2) that interact with unique region(s) of PfPRF at the binding interface. We identified nine-residue peptides from PfACT1 (PLNPKGNRE) and PfACT2 (PLNPKTNRE) that interacted with a unique region of PfPRF. This interaction was largely absent from docked human beta actin-human profilin 1 complex. By molecular docking, the peptide derived from PfACT1 bound at the unique region of the PfPRF interface. Virtual screening based on the peptide-binding region of PfPRF identified a number of drug-like molecules. Our study demonstrated that the unique region of PfPRF could be specifically targeted. Since actin polymerization is essential for parasite motility and invasion, inhibitors specifically targeting parasite actin-profilin interaction could be potential antimalarials.

Malaria parasite Plasmodium falciparum completes its life cycle in vertebrate human and invertebrate mosquito hosts. Inside the mosquito midgut, interaction between ookinete surface expressed P. falciparum enolase (PfENO) and host serine protease plasminogen obtained through blood meal is essential for midgut invasion. Lysine motif on enolases is known to bind to plasminogen through its kringle motifs. A PfENO lysine motif peptide has been shown to inhibit midgut invasion of ookinetes and oocyst development but the region of interaction of plasminogen has not been identified. In this study, attempts were made to identify the region of plasminogen involved in binding to PfENO lysine motif. By protein-protein docking, the lysine motif was found to interact with kringle 4 of plasminogen. Virtual screening based on plasminogen lysine motif binding residues identified a number of peptidomimetics. Molecular docking revealed that the identified peptidomimetics docked on PfENO region containing the lysine motif and hence could be potential blocker of this interaction. Blockade of this interaction could potentially block the development of oocysts and parasite transmission.

2-[(1-Methyl-1H-tetrazol-5-yl)thio]-N'-[(aryl)methylidene/ethylidene]acetohydrazides were synthesized and investigatedin vitroagainst pathogenic bacteriaand Candidaspecies for their antimicrobial activityusing CLSI broth microdilution method. MTT assay was also carried out to evaluate their cytotoxic effects on NIH/3T3 mouse embryonic fibroblast cell lines.2-((1-Phenyl-1H-tetrazol-5-yl)thio)-N'-(1-(pyridin-3-yl)ethylidene)acetohydrazide can be considered as the most promising antibacterial agent againstEnterococcusfaecalis (ATCC 29212) with a MIC value of 100 µg/mL when compared with chloramphenicol (MIC= 200 µg/mL) and low toxicity against NIH/3T3 cells(IC50>500µg/mL).