6^th World Congress on Medicinal Chemistry and Drug Design June 07-08, 2017 Milan,. Italy

N Nadaraia has completed her PhD from Mendeleev Moscow Chemical-Technological Institute. She is a lead research scientist at Tbilisi State Medical University. Her field of interest is a Chemistry and synthesis of biologically active compounds. She is the author of more than 40 papers in reputed journals and has presented at 50 international scientific conferences

Steroidal amines are characterized with wide spectrum of pharmacological activities such as antitumor, anti-inflammatory, antibacterial and anti-arrhythmic activity. On the basis of epiandrosterone acetate, product of transformation of tigogenin (isolated from plant Yucca gloriosa), eight possible epimer of 3-amino-17-hydoxy- and 17-amino-3-hydroxy-5α-androstane have been synthesized and their radioprotective and antiarrhythmic activities have been investigated. Among epimeric aminoalcohols the highest radioprotective activity showed 3β-amino-5α-androstan-3β-ole, while with the highest antiarrhythmic activity is characterized 17β-amino-5α-androstan-3β-ole. Based on these results some conclusion about structure- activity relationship of synthesized compounds could be made. For radioprotective activity more profitable is diaxial orientation of amino- and hydroxy groups; whereas, diequatorial orientation is favorable for the antiarrhythmic activity. Some synthesized of N-alkyl- and N-dialkylamino acetyl derivats of 17β-amino-5α-androststan-3β-ole and 17β-amino-5α-androst-2-ene exhibit antiviral, antitubercular and antitumor activities.

Jane Otado has a doctorate degree from Howard University and post-doctoral studies from the Center of Disease Control and Prevention (CDC). She is an associate director of Regulatory, Ethics, Knowledge and Support (REKS), Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS), a NIH, Clinical and Translational Science Awards (CTSAs). Her research areas include: Understanding informed consent, recruitment/retention, perspectives on genetic testing and research relative African American population and ethnic diverse populations. She is a Member of IRB; and Scientific Review Committee (GHUCCTS). She has extensive experience involving community-based outreach and has worked in clinical trials setting for 13 years.

Objectives: Barriers to participation of African Americans (AA) in clinical trials include lack of awareness about trials, economic factors, mistrust and communication issues. Objectives are: to examine recruitment challenges and experiences; and to determine best practices for researchers to engage AA communities in clinical studies. Methods & Study Population: We reviewed 50 studies conducted at a historically black institution to determine the type, duration and enrollments. A survey was sent to study coordinators to obtain data on recruitment and retention strategies, challenges and dropout rates. We also interviewed 25 study coordinators on challenges and recruitment strategies. Results: Studies range from cross-sectional to prospective. The prospective studies have follow-up periods from 3 to over 24 months. The 22 completed studies achieved recruitment rates of over 50%; 12 had over 100% recruitment rates. For 8 studies with dropouts, the average rate was 23.3%. Barriers: lack of trust, life circumstances, low education, lack of interest; the inability to have study partner. Recruitment strategies include field-based, special advertisements and snowballing. Strategies to barriers are informational sessions, rapport, phone calls and caring attitudes. Discussion: AA seems to be more trusting to participate in a study if their PCP is involved and through community outreach strategies. This is especially true in studies involving medication usage. Minimum risk studies were very successful in recruiting AA<30 years old. Ongoing rapport, caring attitude improves retention rates. Successful recruitment strategies of AA is paramount to better understand how researchers can improve current strategies, thus to increase minority participation in clinical trials.

Szu-Han Chen received her BS in Chemistry from Fu Jen Catholic University in 2008 and her MS degree in Chemistry from National Taiwan Normal University in 2010. She is a PhD student in the Department of Chemistry, National Taiwan University. Her research interests are in total synthesis of drug molecules as well as medicinal and biological chemistry.

Diels–Alder reactions are particularly useful for the total synthesis of pharmacologically active compounds and natural products. Not only does this strategy construct two new C–C σ-bonds in one step, but it also forms a cyclohexene system with good regioand stereo-selectivity up to four contiguous stereocenters. Using heteroatom-substituted electron-rich dienes, such as Danishefsky’s diene, usually promotes the normal electron-demand Diels–Alder reactions in highly regioselective fashion. Tamiflu, the phosphate salt of oseltamivir, is a popular anti-influenza drug in clinical use. Diels–Alder reactions using 1,3-butadiene, 1-timethylsilyoxy-1,3- butadiene, furan, N-Boc-pyrrole and 1-Cbz-1,2-dihydropyridine have been successfully applied to react with appropriate dienophiles for construction of the cyclohexene core structure of oseltamivir. We synthesized a novel diene precursor bearing both 3-pentoxy and ester groups. Dimerization of this diene was overcome by trapping it in situ using activated alkenes as the dienophiles. Inspired by Shibasaki’s work, we successfully synthesized a racemic mixture of oseltamivir via a sequence of reactions that comprise acyl azide formation and Curtius rearrangement. The synthesis of optically active oseltamivir via asymmetric Diels–Alder reaction is currently under investigation.

Wei-Hsin Hsu received her BS from the department of applied chemistry, National Chiao Tung University in Taiwan. Currently, she is a MS student in the department of chemistry, National Taiwan University.

Tuberculosis, a disease caused by bacterial pathogens Mycobacterium tuberculosis, was regarded as under control in the past decades. However, the multi-drug-resistant tuberculosis (MDR-TB) and extensively-drug-resistant tuberculosis (XDR-TB) have emerged to become a serious global health crisis. In 2015, there were an estimated 10.4 million new TB cases worldwide, including nearly a half million cases of MDR-TB. 1 Bedaquiline and Delamanid are the effective drugs for treatment of MDR-TB. However, development of new drugs by targeting different TB proteins is still needed for treatment of the MDR-TB and XDR-TB patients. GlgE is a maltosyl transferase that uses maltose-1-phosphate as the substrate. GlgE involves in a four-step pathway for the production of α-glucan from trehalose, an essential process for mycobacterial survival. Inhibition of GlgE will cause accumulation of maltose 1-phosphate, and trigger the self-poisoning of M. tuberculosis. GlgE becomes an appealing drug target according to the toxic effect and synthetic lethal pathway. As no effective GlgE inhibitor has been discovered, we thus designed and synthesized some potential GlgE inhibitors by mimicking the structure maltose1-phosphate, the GlgE substrate.

Yun Lu received his PhD degree in Organic Chemistry from Nankai University, China in 1996. He did his post-doctoral work in Utah State University with professor Vernon D Parker and Wayne State University with professor Martin Newcomb. His research focuses in the field of physical organic chemistry studying the mechanism of organic reactions and the transition state structures. He is now a professor in the department of chemistry at Southern Illinois University Edwardsville, USA. He has published nearly 50 papers in reputed journals.

About a quarter of the current registered pharmaceutical drugs are enzyme inhibitors. Many of them are the enzyme transitionstate (TS) analogues that are designed largely on the basis of the crystal structure of the stable “frozen” TS analogues or the “still” TS structures from the kinetic studies. Recent decade has, however, witnessed much of the role of the enzyme dynamics in catalysis. Protein vibrations with different time scales have been proposed to assist various processes of the complex enzymatic reactions, including the bond-formation and - cleavage in the active site. The latter suggests a vibrational TS structure on the reaction coordinate, coupled with the local fast motions of enzyme. While study of the vibrational TS that involves the fast fluctuations of the reaction distance is still in its infancy, it would be worthy to consider the concept in design of what may come to be more effective inhibitors and more successful drugs. E.g., a successful inhibitor may be that can also interrupt the TS/enzyme coupled vibrations. In this paper, we present a method to gain the different TS structures at different donor-acceptor distance (DAD) in both solution and enzymatic H-transfer reactions. We use secondary (2°) kinetic isotope effect (KIE) as a structural descriptor. We determine the 2° KIEs and thus TS structures for hydride- and deuteride-tunneling processes that have different DADs. Information about the DADdependent TS structures in enzymes would help track the path of the vibrational TS conformational changes. This information would be useful for drug design.

Anna Golovan, D K Zabolotny Institute of Microbiology and Virology - NASU, Ukraine.

Antiviral drugs mainly targeted onto prevention of viral synthesis within the host cells or elimination of it enters into the cell through induction of natural defense mechanisms, among which are immune response and interferon synthesis. Recently, it was suggested that human microbiota may play a role in virus infection. Human viruses did not infect bacteria cells, but this does not exclude a possibility of bacteria participation in the virus propagation into the host cells. An interaction of lactic acid bacteria with human adenovirus serotype 5 (HAdV-C5) was studied. We used strains of bacteria some of which are normally can be found in human intestine, while others are supplied with various milk products: Lactobacillus plantarum (56 strains), Enterococcus spp. (23 strains), Leuconostoc spp. (14 strains), Lactococcus lactis (3 strains) and Pediococcus spp. (1 strain). After 1 h of interaction of viruses (VPs) with bacteria the samples were examined with electron microscopy. In 17% of cases there were no VPs found that can suggest their total destruction, but in other cases the VPs were clearly seen performing well preserved viruses and viral proteins. The direct viral adhesion to the surface of bacteria was noticed for 23% of the strains, while in other cases the VPs were associated with extracellular matrix structures or as the free particles. The current research is one of the first steps in understanding the role of microbiota in the virus infections development. It showed that various strains of the same bacterial species can cause opposite effects and lead both to the virus degradation or preservation and, therefore, can prevent or help virus to enter the human cells.

Daniel Ehrsam has done his graduation in Pharmaceutical Sciences from the University of Basel in 2014. He did his master’s research work on brain ischemia pathways under supervision of Dr. Margaret Weiss at Texas Tech Health Science Center. He has worked at the Swiss Tropical and Public Health Institute on helminth drug development. In 2015, he joined the research group of professor Dr. Henriette E Meyer zu Schwabedissen for his PhD studies. His research is focused on the development of an enzyme based targeted drug delivery system.

In order to spare healthy cells and decrease adverse effects, innovative concepts of tumor targeting aim at bringing the cytotoxic payload most selectively to tumor cells is needed. One concept is to use enzymes overexpressed in the surrounding of proliferating cells, like the gelatinase matrix-metalloproteinase 9 (MMP-9), as a trigger for drug release. Our aim is to synthesize and characterize self-assembling nano-formulations consisting of an MMP9-labile peptide coupled to an anti-cancer drug. By use of bio-conjugate chemistry an amphiphilic molecule containing paclitaxel and an MMP9-labile peptide was synthesized to form nanoparticles. To identify a tumor entity as a target for our novel nano-formulation we quantified expression of MMP-9 in a commercially available tissue collection by multiplex real-time PCR. Several tumor entities showed significantly increased expression comparing normal to malignant tissue. Immunohistochemistry and database analysis suggested brain tumors, particularly glioblastoma multiforme, as a tumor entity where MMP-9 could be used to trigger drug release. Established brain cancer cell lines were characterized for MMP-9 expression and activity. LN-18 and U87-MG cells were selected for in vitro characterization of the synthesized nano-formulation. In preparation of in vivo xenograft studies LN-18 and U87-MG cells were stably transfected with mKate2 and characterized for expression. Taken together, we verified overexpression of MMP9 in glioblastoma multiforme. Commonly used brain cancer cell lines were characterized prior to in vitro studies on MMP9 triggered drug release, and preparations for in vivo xenograft studies have been finished. Further studies are needed to fully characterize the nano-formulation and understand its effects in vivo.

Mohamed A El-Atawy has completed his PhD in organic chemistry, department of chemistry, University of Milan, Italy. Currently, he is working as an Assistant Professor in Alexandria University, Egypt.

Pyrrole nucleus is one of the most important heterocycles abundantly found in bioactive natural molecules, forming the characteristic subunit of heme, chlorophyll vitamin B12 as well as in melanin pigments. 1,2,5-Trisubstituted pyrroles display interesting biological properties, such as anti-inflammatory, antipsychotic, spasmolytic and radioprotective. Two clinical examples of pyrroles displaying this pattern of substitution are amtolmetin and tolmetin (non-steroidal anti-inflammatory agents). Generally, pharmaceuticals containing pyrroles are of high value as biological agents such as sunitinib (anti-tumor), ketorolac (analgesic) and the highly successful cholesterol-lowering drug atorvastatin calcium (Lipitor), which is notable as the first drug to earn in excess of $1 billion of sales in its first year. The electronic properties of pyrrole are important in the context of conducting polymers, where poly-pyrroles have found many useful applications. Herein, we report a new and facile method for the synthesis of 2,5-di and 2,3,5-trisubstituted pyrrole using intramolecular reductive cyclization of the easily accessible nitrodienes as starting material catalyzed by palladium complex and with carbon monoxide as a reductant.

Q B C Francisco Humberto González Gutiérrez has completed his licentiate from Universidad de Sonora. He has done his Master’s in faculty of biological sciences and health from Universidad de Sonora. He has two articles published as co-author, participated in multiple school events where he obtained recognition for obtaining first places and in addition to having the participation in a congress at state level.

Studies on resin of Bursera microphylla showed that it consist mainly of terpenes; these compounds have been proved to be active against cancer cell lines. Cancer is a public health problem worldwide. Compounds of Bursera microphylla showed antiproliferative activity in cancer cell lines. Therefore, knowledge of the action mechanism for future drugs against cancer is required. The aim of this study was to determine the molecular mechanisms of the compounds that displayed antiproliferative activity on human cancer cell line A549 derived from B. microphylla resin. The apoptotic activity was measured through annexin V staining and propidium iodide (PI). The breakdown of the mitochondrial membrane potential was measured using the cationic lipophilic fluorochrome JC-1. Determination of cell arrest will be quantified by measuring the amount of genetic material (DNA) using PI. To evaluate the apoptotic induced pathway, caspase activity will be measured using fluorescein staining of active caspase. An apoptotic activity of the dihydroclusin diacetate, betulonic acid, microphyllanin, malabaricatrienol, ariensin and β-caryophyllene molecules of 22.64%, 4.02%, 1.45%, 25.6%, 13.02% and 10.45%, respectively was obtained and a percentage loss of mitochondrial membrane potential of up to 97% and a caspase activity of up to 3.5 fold. Beta caryophyllene, ariensin and betulonic acid induce arrest in G2/M phase; dihydroclusine acetate in S phase and microphyllanin in G0/G1. The ability to induce the apoptosis of the compounds through the caspase pathway, cell cycle arrest and activated by the intrinsic pathway was demonstrated.

Arianna Gelain graduated in Medicinal Chemistry and Technology and achieved her PhD degree in Medicinal Chemistry at University of Milan. She is researcher at Departement of Pharmaceutical Science and assistant professor at faculty of pharmacy. She is co-author of 31 papers, 6 reviews, published in peer reviewed journals and 1 book chapter.

During our ongoing studies, focused on the identification of novel potential anticancer agents inhibiting STAT3 (Signal Transducer and Activator of Transcription 3)1, we synthesized some new 1,2,5-oxadiazole ligands for Pt (II) complexes formation2. In particular ligand 3·HCl exhibited cytotoxicity on HCT116 cells (IC50 = 95.2 μM) and a selective interaction with STAT3 (IC50 = 8.2 μM) respect to STAT1 (IC50> 30 μM). The related platinum complex Pt-3 showed an increased cytotoxic effect (IC50 = 18.4 μM) and a higher interaction with STAT3 (IC50 = 1.4 μM). Noteworthy Pt-3, tested on syngeneic murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice, exhibited an interesting antitumor activity with fewer side effects than cisplatin.

Arianna Gelain graduated in Medicinal Chemistry and Technology and achieved her PhD degree in Medicinal Chemistry at University of Milan. She is researcher at Departement of Pharmaceutical Science and assistant professor at faculty of pharmacy. She is co-author of 31 papers, 6 reviews, published in peer reviewed journals and 1 book chapter.

Methionine aminopeptidase (MetAP) carries out an essential function of protein N-terminal processing in many bacteria and is a promising target to develop novel antitubercular agents. MetAP is divided into two subtypes, namely type 1 and type 2. Eukaryotic cells have both subtypes, and prokaryotic cells have only one, which codes for a type 1 MetAP. Mycobacterium tuberculosis has two MetAP genes and both belong to type 1 MetAP: MtMetAP1a and MtMetAP1c, which are essential for its in vivo survival and pathogenicity1. As furan-based compounds have shown to be promising antitubercular agents as MetAPs inhibitors2, we planned the design and synthesis of new derivatives functionalizing 2 and 5 positions of the furane ring (Figure 1), starting from our hit compound, MM40. This latter is the most potent competitive MbtI inhibitor to date identified and exhibited a promising antibiotic activity. MbtI is the salicylate synthase from Mycobacterium tuberculosis which catalyzes the first step in mycobactins biosynthesis, that is a validated target for fighting tuberculosis3. These compounds could be synergically able to act on MetAPs and MbtI, leading to new antituberculars.