Novel Biginelli dihydropyrimidines with potential anticancer activity: A parallel synthesis and CoMSIA study

Novel Biginelli dihydropyrimidines of biological interest were prepared using p-toluene sulphonic acid as an efficient catalyst. All the thirty-two synthesised dihydropyrimidines were evaluated for their in vitro antioxidant activity using DPPH method. Only, compounds 28 and 29 exhibited reasonably good antioxidant activity. Furthermore, the synthesised Biginelli compounds were subjected for their in vitro anticancer activity against MCF-7 human breast cancer cells. The title compounds were tested at the concentration of 10 μg. Compounds exhibited activity ranging from weak to moderate and, from moderate to high in terms of percentage cytotoxicity. Among them, compounds 10 and 11 exhibited significant anticancer activity. In order to elucidate the three-dimensional structure–activity relationships (3D QSAR) towards their anticancer activity, we subjected them for comparative molecular similarity indices analysis (CoMSIA). Illustration regarding their synthesis, analysis, antioxidant activity, anticancer activity and 3D QSAR study is described.

An ethnobotanical study of traditional anti-inflammatory plants used by the Lohit community of Arunachal Pradesh, India

Aim of the study: Most people especially in rural areas depend on herbal medicines to treat many diseases including inflammation-related ailments such as rheumatism, muscle swelling, cut wound, accidental bone fracture, insect bites, pains and burn by fire and hot water. The objectives of this study were: to catalog ethno-medicinal plants of Lohit community, ecological status, indigenous folk medicinal uses, morphological parts used and to determine their reported pharmacological studies. Materials and methods: The ethnobotanical information on traditional medicinal plants exclusively used for management of inflammation-related ailments by the Khampti community of Arunachal Pradesh, India was based on first-hand field survey work through semi-structured interviews. Results and conclusion: A total of 34 species in 32 genera and 22 families were encountered during the field survey. Botanical families such as Asteraceae, Euphorbiaceae, Zingiberaceae and Lamiaceae were represented by the highest numbers of species reported in this study. Thirteen plant species, namely: Bombax ceiba, Canarium strictum, Chloranthus erectus, Xanthium indicum, Lycopodium clavatum, Coleus blumei, Batrachospermum atrum, Chlorella vulgaris, Marchantia palmata, Marchantia polymorpha, Eria pannea, Sterculia villosa and Alpinia galanga are reported for the first time for the treatment of inflammation-related diseases.

Structure-Based Design of DevR Inhibitor Active against Nonreplicating Mycobacterium tuberculosis

Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A phenylcoumarin derivative (compound 10) identified by in silico pharmacophore-based screening of 2.5 million compounds employing protocols with some novel features including a water-based pharmacophore query, was characterized further. Compound 10 inhibited DevR binding to target DNA, down-regulated dormancy genes transcription, and drastically reduced survival of hypoxic but not nutrient-starved dormant bacteria or actively growing organ ` isms. Our findings suggest that compound 10 ``locks'' DevR in an inactive conformation that is unable to bind cognate DNA and induce the dormancy regulon. These results provide proof-of-concept for DevR as a novel target to develop molecules with sterilizing activity against tubercle bacilli.

Gabapentin: A Stereochemically Constrained gamma Amino Acid Residue in Hybrid Peptide Design

Nature has used the all-alpha-polypeptide backbone of proteins to create a remarkable diversity of folded structures. Sequential patterns of 20 distinct amino adds, which differ only in their side chains, determine the shape and form of proteins. Our understanding of these specific secondary structures is over half a century old and is based primarily on the fundamental elements: the Pauling alpha-helix and beta-sheet. Researchers can also generate structural diversity through the synthesis of polypeptide chains containing homologated (omega) amino acid residues, which contain a variable number of backbone atoms. However, incorporating amino adds with more atoms within the backbone introduces additional torsional freedom into the structure, which can complicate the structural analysis. Fortunately, gabapentin (Gpn), a readily available bulk drug, is an achiral beta,beta-disubstituted gamma amino add residue that contains a cyclohexyl ring at the C-beta carbon atom, which dramatically limits the range of torsion angles that can be obtained about the flanking C-C bonds. Limiting conformational flexibility also has the desirable effect of increasing peptide crystallinity, which permits unambiguous structural characterization by X-ray diffraction methods. This Account describes studies carried out in our laboratory that establish Gpn as a valuable residue in the design of specifically folded hybrid peptide structures. The insertion of additional atoms into polypeptide backbones facilitates the formation of intramolecular hydrogen bonds whose directionality is opposite to that observed in canonical alpha-peptide helices. If hybrid structures mimic proteins and biologically active peptides, the proteolytic stability conferred by unusual backbones can be a major advantage in the area of medicinal chemistry. We have demonstrated a variety of internally hydrogen-bonded structures in the solid state for Gpn-containing peptides, including the characterization of the C-7 and C-9 hydrogen bonds, which can lead to ribbons in homo-oligomeric sequences. In hybrid alpha gamma sequences, district C-12 hydrogen-bonded turn structures support formation of peptide helices and hairpins in longer sequences. Some peptides that include the Gpn residue have hydrogen-bond directionality that matches alpha-peptide helices, while others have the opposite directionality. We expect that expansion of the polypeptide backbone will lead to new classes of foldamer structures, which are thus far unknown to the world of alpha-polypeptides. The diversity of internally hydrogen-bonded structures observed in hybrid sequences containing Gpn shows promise for the rational design of novel peptide structures incorporating hybrid backbones.

Synthesis of new 4-isopropylthiazole hydrazide analogs and some derived clubbed triazole, oxadiazole ring systems - A novel class of potential antibacterial, antifungal and antitubercular agents

In the present study a series of 4-isopropylthiazole-2-carbohydrazide analogs, derived clubbed oxadiazole-thiazole and triazole-thiazole derivatives have been synthesized and characterized by IR, H-1 NMR, C-13 NMR, elemental and mass spectral analyses. The synthesized compounds were evaluated for their preliminary in vitro antibacterial, antifungal and antitubercular activity against Mycobacterium tuberculosis H(37)Rv strain by broth dilution assay method. The synthesized compounds 7a, 7b, 7d and 4 showed an antitubercular efficacy considerably greater than that of the parent 4-isopropyl-1,3-thiazole-2-carbohydrazide 1, suggesting that the substituted 4-isopropylthiazole-2-carbohydrazide moiety plays an important role in enhancing the antitubercular properties of this class of compounds. Compounds 2c, 3, 4, 6d, 7a and 7b exhibited good or moderate antibacterial and antifungal activity. Compounds 4 and 7b showed appreciable cytotoxicity at a concentration of 250 mu M.

Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity

Sirtuins are NAD(+) dependent deacetylases that modulate various essential cellular functions. Development of peptide based inhibitors of Sir2s would prove useful both as pharmaceutical agents and as effectors by which downstream cellular alterations can be monitored. Click chemistry that utilizes Huisgen's 1,3-dipolar cycloaddition permits attachment of novel modifications onto the side chain of lysine. Herein, we report the synthesis of peptide analogues prepared using click reactions on N epsilon-propargyloxycarbonyl protected lysine residues and their characterization as inhibitors of Plasmodium falciparum Sir2 activity. The peptide based inhibitors exhibited parabolic competitive inhibition with respect to acetylated-peptide substrate and parabolic non-competitive inhibition with NAD(+) supporting the formation of EI2 and E.NAD(+).I-2 complexes. Cross-competition inhibition analysis with the non-competitive inhibitor nicotinamide (NAM) ruled out the possibility of the NAM-binding site being the second inhibitor binding site, suggesting the presence of a unique alternate pocket commodating the inhibitor. One of these compounds was also found to be a potent inhibitor of the intraerythrocytic growth of P. falciparum with 50% inhibitory concentration in the micromolar range.

Synthesis and Evaluation of a Novel Class of G-Quadruplex-Stabilizing Small Molecules Based on the 1,3-Phenylene-Bis(piperazinyl benzimidazole) System

Achieving stabilization of telomeric DNA in G-quadruplex conformation by Various organic compounds has been an important goal for the medicinal chemists seeking to develop new anticancer agents. Several compounds are known to stabilize G-quadruplexes. However, relatively few are known to induce their formation and/or alter the topology, of the preformed quadruplex DNA. Herein, four compounds having the 1,3-phenylene-bis(piperazinyl benzimidazole) unit as a basic skeleton have been synthesized, and their interactions with the 24-mer telomeric DNA sequences from Tetrahymena thermophilia d(T(2)G(4))(4) have been investigated using high-resolution techniques Such as circular dichroism (CD) spectropolarimetry, CD melting, emission spectroscopy, and polyacrylamide gel electrophoresis. The data obtained, in the presence of one of three ions (Li+, Na+, or K+), indicate that all the new compounds have a high affinity for G-quadruplex DNA, and the strength of the binding with G-quadruplex depends on (1) phenyl ring substitution, (ii) the piperazinyl side chain, and (iii) the type of monovalent cation present in the buffer. Results further Suggest that these compounds are able to abet the conversion of the Intramolecular quadruplex into parallel stranded intermolecular G-quadruplex DNA. Notably, these compounds are also capable of inducing and stabilizing the parallel stranded quadruplex from randomly structured DNA in the absence of any stabilizing cation. The kinetics of the structural changes Induced by these compounds could be followed by recording the changes in the CD signal as a function of time. The implications of the findings mentioned above are discussed in this paper.

The potential of certification for conservation and management of wild MAP resources

Medicinal and aromatic plants (MAPs) are an integral part of our biodiversity. In majority of MAP rich countries, wild collection practices are the livelihood options for a large number of rural peoples and MAPs play a significant role in socio-economic development of their communities. Recent concern over the alarming situation of the status of wild MAP resources, raw material quality, as well as social exploitation of rural communities, leads to the idea of certification for MAP resource conservation and management. On one hand, while MAP certification addresses environmental, social and economic perspectives of MAP resources, on the other hand, it ensures multi-stakeholder participation in improvement of the MAP sector. This paper presents an overview of MAP certification encompassing its different parameters, current scenario (Indian background), implementation strategies as well as stakeholders’ role in MAP conservation. It also highlights Indian initiatives in this direction.

Fish stupefying plants used by the Gond tribal of Mendha village of Central India

Fish stupefying plants and their methods of use by the Gond people of Mendha village of the Gadchiroli district in Maharashtra state have been documented. For the purpose of validation, literature survey revels that many fish stupefying plants being used since long time by local people are recently well tested by many workers and are found to have many important medicinal properties. It was also observed that herbal fish stupefying agents are excellent means of fishing, which do not kill whole fish stock like chemicals.

Design, synthesis, and application of novel triclosan prodrugs as potential antimalarial and antibacterial agents

A number of new triclosan-conjugated analogs bearing biodegradable ester linkage have been synthesized, characterized and evaluated for their antimalarial and antibacterial activities. Many of these compounds exhibit good inhibition against Plasmodium falciparum and Escherichia coli. Among them tertiary amine containing triclosan-conjugated prodrug (5) inhibited both P. falciparum (IC50; 0.62 μM) and E. coli (IC50; 0.26 μM) at lower concentrations as compared to triclosan. Owing to the presence of a cleavable ester moiety, these new prodrugs are hydrolyzed under physiological conditions and parent molecule, triclosan, is released. Further, introduction of tertiary/quaternary functionality increases their cellular uptake. These properties impart them with higher potency to their antimalarial as well as antibacterial activities. The best compound among them 5 shows close to four-fold enhanced activities against P. falciparum and E. coli cultures as compared to triclosan.

Design of mechanism-based inhibitors of transthyretin amyloidosis:Studies with biphenyl ethers and new structural templates

Transthyretin (TTR), a tetrameric thyroxine (T4) carrier protein, is associated with a variety of amyloid diseases. In this study, we explore the potential of biphenyl ethers (BPE), which are shown to interact with a high affinity to its T4 binding site thereby preventing its aggregation and fibrillogenesis. They prevent fibrillogenesis by stabilizing the tetrameric ground state of transthyretin. Additionally, we identify two new structural templates (2-(5-mercapto-[1,3,4]oxadiazol-2-yl)-phenol and 2,3,6-trichloro-N-(4H-[1,2,4]triazol-3-yl) represented as compounds 11 and 12, respectively, throughout the manuscript) exhibiting the ability to arrest TTR amyloidosis. The dissociation constants for the binding of BPEs and compound 11 and 12 to TTR correlate with their efficacies of inhibiting amyloidosis. They also have the ability to inhibit the elongation of intermediate fibrils as well as show nearly complete (> 90%) disruption of the preformed fibrils. The present study thus establishes biphenyl ethers and compounds 11 and 12 as very potent inhibitors of TTR fibrillization and inducible cytotoxicity.

Synthesis and bioassay of a new class of heterocycles pyrrolyl oxadiazoles/thiadiazoles/triazoles

A new class of heterocycles pyrrolyl thiadiazoles, pyrrolyl oxadiazoles and pyrrolyl triazoles were prepared from arylsulfonylethenesulfonylacetic acid methyl ester and tested for their antimicrobial and cytotoxic activities. (C) 2008 Elsevier Masson SAS. All rights reserved.

Synthesis, spectral characterization, in-vitro microbiological evaluation and cytotoxic activities of novel macrocyclic bis hydrazone

A macrocyclic hydrazone Schiff base was synthesized by reacting 1,4-dicarbonyl phenyl dihydrazide with 2,6-diformyl-4-methyl phenol and a series of metal complexes with this new Schiff base were synthesized by reaction with Co(II), Ni(II) and Cu(II) metal salts. The Schiff base and its complexes have been characterized by elemental analyses, IR, H-1 NMR, UV-vis, FAB mass, ESR spectra, fluorescence, thermal, magnetic and molar conductance data. The analytical data reveal that the Co(II), Ni(II) and Cu(II) complexes possess 2:1 metal-ligand ratios. All the complexes are non-electrolytes in DMF and DMSO due to their low molar conductance values. Infrared spectral data suggest that the hydrazone Schiff base behaves as a hexadentate ligand with NON NON donor sequence towards the metal ions. The ESR spectral data shows that the metal-ligand bond has considerable covalent character. The electrochemical behavior of the copper(II) complex was investigated by cyclic voltammetry. The Schiff base and its complexes have also been screened for their antibacterial (Escherichia coli, Staphylococcus aureus, Shigella dysentery, Micrococcus, Bacillus subtilis, Bacillus cereus and Pseudomonas aeruginosa) and antifungal activities (Aspergillus niger, Penicillium and Candida albicans) by MIC method. The brine shrimp bioassay was also carried out to study their in-vitro cytotoxic properties. (C) 2009 Elsevier Masson SAS. All rights reserved.

Facile one-pot synthesis of thio and selenourea derivatives: A new class of potent urease inhibitors

A facile, one-pot synthesis of thio and selenourea derivatives from amines using tetrathiomolybdate 1 and tetraseleno-tungstate 2 as sulfur and selenium transfer reagents, respectively, is reported. The compounds were tested for their activity as urease inhibitors and some of the compounds showed potent activity in the nanomolar range towards jack bean urease. (C) 2007 Elsevier Ltd. All rights reserved.

Conformationally locked thiosugars alpha-mannosidase inhibitors: Synthesis, and docking studies as potent biochemical

series of thiosugar derivatives (thiolevomannosans) derived from mannose were synthesized and their inhibitory activity was tested against alpha-mannosidase (jack bean). These inhibitors were found to be more potent than the well-known inhibitors like kifunensine and deoxymannojirimycin based on docking and biochemical studies. The sulfone derivative 10 was shown to be the best inhibitor of alpha-mannosidase with the K-i value of 350 nM. (c) 2007 Elsevier Ltd. All rights reserved.