Medicinal Chemistry

In this paper we reported the synthesis of novel series of 5-[1,3-bis (4- substituted phenyl) prop-2-en-1-ylidene]- 2-thioxodihydropyrimidine-4,6(1H, 5H)-diones (5a-k). The target compounds were synthesized by the Knoevenagel condensation of different chalcones (3a-k) with thiobarbituric acid using acetic acid as a catalyst in ethanol. These compounds were screened for their antimicrobial and antioxidant activities. From antimicrobial activity results it was found that compounds 5e, 5i and 5k displayed good antibacterial and antifungal activity against all tested strains. Further, the selected compounds were studied for docking using the enzyme, Glucosamine-6-phosphate synthase and the compounds 5a, 5e and 5k have emerged as an active antimicrobial agents with least binding energy (-4.52 and -4.41 kJ mol-1). Compounds 5c and 5f showed promising free radical scavenging and Fe+2 ion chelating activity.

Epstein-Barr virus (EBV) is causally associated with multiple cancers of epithelial and lymphoid origin. Generally, EBV establishes a lifelong quiescent homeostasis (latency) exerting its immune modulating and oncogenic properties only under certain conditions. Lytic replicative EBV infection is restricted to differentiated oropharyngeal epithelia and plasma B-cells. In EBV-associated tumor cells viral gene expression is limited to defined latency programs, without overt virus "lytic" replication. Artificial triggering of EBV lytic replication with chemical agents (drugs) forms the basis of cytolytic virus activation (CLVA) therapy currently under clinical investigation for treating EBV-positive malignancies. Reactivation from latency requires expression of viral transactivator proteins BZLF1 (Zta) and BRLF1 (Rta). In tumor cells, the BZLF1 promoter (Zp) is highly methylated and generally inactive. However, Zp can be triggered into a self-enhancing activation loop in response to chemical or biological agents, including cytostatic drugs and epigenetic modifiers. This process is orchestrated by Zp-binding cellular transcription factors, such as myocyte enhancer factor 2 (MEF2), specificity protein 1 (SP1), and zinc finger E-box binding homeobox (ZEB) proteins. Understanding the mechanism of lytic induction by chemical inducers is essential for developing effective therapies. This review provide a short overview of EBV biology and will focus on branded and novel agents (drugs) used for EBV lytic induction and discuss molecular mechanisms by which the EBV lytic switch is triggered and controlled.

Background: The wide use of the antibiotics resulted in the serious medical problem of drugs resistance and public health concern. Preparation of new synthetic derivatives of antibiotics with novel mechanism of action has become an important task to cope with drug resistanceproblems.

Objectives: The goal of the present study is to prepare a family of new metal(II) coordination compounds of Mn, Co, Ni, Cu and Zn with a Schiff base (HL) derived from the condensation of cephalexin antibiotic with 1,6-hexanediamine and to investigate the antibacterial activity of the free cephalexin and the synthesized complexes against gram positive and gram negative strains.

Methods: Several physicochemical and spectroscopic methods including elemental and thermal analysis, molar conductance and magnetic susceptibility measurements, electronic, FT-IR, EPR and 1H NMR spectral and modelling studies, were used to find out the stoichiometry and binding mode of these complexes. Free cephalexin and cephalexin Schiff base complexes have been screened for antibacterial activity by agar diffusion disc method.

Results: The Schiff base ligand HL behaves as a monoanionic tridentate NNO chelating agent. The mode of bonding and the geometry of the coordination compounds have been confirmed on the basis of spectral and magnetic data which suggested an octahedral geometry for all the complexes. Based on these studies, the general formulae [M(L)(H2O)3][PF6] are proposed for the complexes. The characterization methods revealed that the investigated cephalexin exhibited modification in both solubility and antibacterial activity when they interacted with the metal ions under study. The solubility of cephalexin was remarkably decreased in most of the commonly used solvents on its complexation. The antibacterial activity results indicate that while some of the complexes had more bactericidal activity against some bacteria than the free cephalexin, other complexes exhibited less antibacterial activity.

Conclusions: The antibacterial activity of cephalexin was affected on complexation with metal ions. It was found that the synthesized novel metal complexes are more toxic than the free cephalexin and exhibited promising bactericidal activity against E. coli, S. aureus and K. pneumonia.

Some 2,5-disubstituted-1,3,4-oxadiazole derivatives have been synthesized conveniently via oxidative cyclization of various synthesized aroylhydrazones by (diacetoxyiodo)benzene in dichloromethane under mild reaction conditions. In addition, the effect of electron-withdrawing/releasing groups on the formation of oxadiazole nucleus has also been studied. Compounds were obtained in good yields and their structures have been established on the basis of their FT-IR, 1H, 13C NMR and mass spectral data. Herein, a total of 42 compounds (hydrazones as well as oxadiazoles) were synthesized and investigated for their DNA photocleavage potential using plasmid DNA. It has been observed that aroylhydrazones showed good DNA photocleavage activity in comparison to their corresponding oxadiazoles.

In vitro anti-mycobacterial activities of dispiropyrrolidine derivatives along with their intermediates bisarylidene piperidones were investigated through high throughput screen. Our results revealed that dispiropyrrolidines possess promising activity against Mtb H37Rv. Compound 4g, 1-Methyl-4-(2,4-dichlorophenyl)pyrrolo-(spiro[2.3″]oxindole)- spiro[3.3′]-5′-(2,4-dichlorophenylmethylidene)piperidin-4′-one emerged as the most active antimycobacterial agent having EC50 of 2.46 μM and MIC at 10 μM against MTB-H37Rv.

N-butyl-1-deoxynojirimycin (NB-DNJ) based on imino sugars Deoxynojirimycin (DNJ) has been approved for treatment of Gaucher’s disease. Here, an improved synthetic procedureof NB-DNJ was described. High yields can be achieved during the introduction steps of n-butyl by combining a strong nucleophilicity of imine in the iminosugar andan easy leaving group methanesulfonatein butyl, which is much higher than the similar reported procedures. This method can be served as an excellent solution to the synthesis of various N-alkyl substituted chain DNJ, even applied to large-scale production.

Metastasis is the major cause of death in colorectal cancer (CRC) patients. Circulating tumor cells (CTCs) are the biologic correlate of metastasis. Despite the clinical relevance of CTCs, there has been little progress in understanding their biology in detail; particularly the phenotype of CTCs with metastasis-forming capacities is still unknown. In this article we discuss the benefits and limitations of mouse models of CRC-derived CTCs.

Five new phenolic glycosides, liparisglycoside K-O (1-5) and one known compound, 4-allyl-2,6-dimethoxyphenol glucoside (6) were isolated from the whole plant of Liparis odorata. Compound 6 was isolated and identified from this genus for the first time. The structures of all compounds were elucidated through extensive spectroscopic methods including UV, IR, MS, 1D- and 2D-NMR. All compounds from Liparis odorata were evaluated for their ability to inhibit LPS-induced NO production on the BV2 microglial cell line in vitro, as well as their inhibitory effects on PTP1B and α-glucosidase enzyme assays.

A series of polyhydroxycoumarin derivatives, that are analogs of naturally occurring compounds, have been synthesized and their antioxidant activity (AOA) examined using DPPH, ABTS, and in vitro lipid peroxidation inhibition assays. The SAR for differently substituted polyhydroxycoumarins is reported by evaluating the positional effect of hydroxyl groups and the effect of incorporation of the lipophilic group on antioxidant activity. Many of the compounds synthesized have 4-5 fold higher AOA than ‘Trolox’ taken as standard. In DPPH and ABTS assays, the trihydroxycoumarins were observed to have a potent antioxidant activity. It has been observed that alkylation at C-3/C-4 position as well as the incorporation of pyran ring on coumarin skeleton led to the reduction in AOA in the above two assays. However, in lipid peroxidation inhibition assay an enhancement in AOA was observed for such modifications. The rationale for the observance of variation in AOA in different assays is also studied.

Angiogenesis is a vital process in the progression of cancer as it also play a key role in tumor transition from its dormant state to a malignant stage. VEGF is key growth factor plays an important role in angiogenesis and is regulated by transcription factor HIF-1α. Natural compounds derived from plants have been a prime source for numerous clinically useful anti-cancer agents specially for targeting neo-angiogenesis. Medicinal plants continue to play a central role in the healthcare system of large proportions of the world’s population, particularly true in developing countries like India. In the current report, we studied the angio suppressive
effect of aqueous extract of Clitoria ternatea in EAC cells induced angiogenesis. In vivo anti-angiogenic effect of C. ternatea was demonstrated by the down regulation of VEGF secretion from Ehrlich ascites carcinoma (EAC) cells and inhibition of blood vessels formation indicating the potential angio suppressive effect of plant. HIF-1α protein, a transcription factor known to be key a regulator in hypoxia-induced angiogenesis was also down regulated by C. ternatea. Our invetigation indicated that, HIF-1α nuclear sequestration is repressed by C. ternatea through inhibition of nuclear translocation. We hypothesize that decreased levels of HIF-1α in the nucleus of EAC cells upon MECT treatment could be responsible for decreased expression of VEGF which is also attributed to the angio-suppressive effects of MECB. C. ternatea promises to be a potential anti-angiogenic plant which can be exploited to treat cancer.

Hepatitis B virus (HBV) infection is a serious worldwide health problem as drugs (such as lamivudine and adefovir) for treating HBV are still unsatisfactory, due to high recurrence, drug resistance and inevitable side effects. Therefore, there exists a significant medical need to explore novel classes of drugs with different antiviral targets and mechanisms for anti-HBV purposes. Recently, some non-nucleoside HBV inhibitors with specific targets have been obtained from natural sources or prepared by synthesis. These compounds provide useful information for developing novel non-nucleoside compounds as anti-HBV agents.