RECENT DEVELOPMENTS AND MULTIPLE BIOLOGICAL ACTIVITIES AVAILABLE WITH 1, 8-NAPHTHYRIDINE DERIVATIVES: A REVIEW

Within the wide range of nitrogen-containing heterocyclic compounds, the derivatives of 1,8-naphthyridine (NPTR) have gained a rising interest due to their reported versatile biological activities. The derivatives of NPTR scaffold are found to invite special interest from researchers nowadays on the significance of their manifestations of multiple attractive pharmacological activities which establish them as an effective and versatile tool in pharmaceutical chemistry and drug discovery. The diverse biological activities mainly include anti-inflammatory, antimicrobial, antiviral, anticancer, antihypertensive and analgesic activities. Novel NPTR scaffold has emerged its potency to treat neurological diseases like depression and Alzheimer's disease. Further these agents possess different inhibitory activities, such as anti-HIV, anti-osteoporotic, αvβ3 antagonism, antimalarial, platelet aggregation, anti-oxidant, anti-allergic, gastric antisecretory, anticonvulsant, epidermal growth factor receptor (EGFR) inhibition, protein kinase inhibition, ionotropic properties, β3 antagonism, phosphodiesterase 4 (PDE 4) inhibitions, adenosine receptor agonistic activity, adrenoceptors antagonism and DNA stabilizing activity, etc. In this review, we highlight the updates of different 1,8-naphthyridine derivatives and explain the key data available in the context of various biological activities of NPTR derivatives available from the literature. This may direct opportunity in researches in the synthesis of novel medicinal agents and the development of new heterocycles for modification of existing biological actions as well as evaluation of other possible pharmacological activities

An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities

Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. In the last years, these natural compounds have been gaining an increasing attention from the scientific community for their wide range of biological activities, mainly due to their ability to interact with diverse enzymes and receptors in living organisms. In addition, coumarin nucleus has proved to be easily synthetized and decorated, giving the possibility of designing new coumarin-based compounds and investigating their potential in the treatment of various diseases. The versatility of coumarin scaffold finds applications not only in medicinal chemistry but also in the agrochemical field as well as in the cosmetic and fragrances industry. This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches

Dérivés lipophiles de la ciprofloxacine et de la lévofloxacine : synthèse et évaluation de leurs activités antibactérienne, antimycobactérienne et antiproliférative

La ciprofloxacine (CIP) et la lévofloxacine (LEV) appartiennent à la large famille des antibiotiques de type fluoroquinolone (FQ). Ce sont des agents antibactériens qui ont également été recommandés pour le traitement de la tuberculose. Malgré tous leurs avantages, l'apparition des phénomènes de résistance dans les souches pathogènes bactériennes et M. tuberculosis devient un problème majeur. C'est pourquoi, le besoin de développer de nouveaux agents existe toujours. Des études ont montré que CIP et LEV ont des activités antiproliférative et apoptotique contre plusieurs lignées de cellules cancéreuses. Le mécanisme exact de cette activité des FQs est inconnu, mais il a été prouvé qu'ils peuvent inhiber la topoisomérase II mammifère, les G-quadruplex, et la polymérisation de tubuline. De plus, nous avons mis en évidence que certains dérivés lipophiles de la CIP possèdent une activité antiproliférative. Le greffage de longues chaînes alkyles pourrait donc conduire à des agents anticancéreux. Au cours de cette thèse, nous avons développé et synthétisé cinq séries des dérivés lipophiles de la CIP et de la LEV. Afin de contourner les difficultés synthétiques rencontrées (en particulier la faible réactivité de l'acide carboxylique en C-3 du motif quinolone) nous avons réalisé différents essais d'optimisation des conditions réactionnelles. L'influence de différents paramètres a été étudiée (des réactions ont été conduites sous microondes, en présence ou absence de catalyseur) ce qui nous a permis d'améliorer les rendements et de réduire le temps de réaction. Les activités biologiques des cinq séries de dérivés ont été évaluées in vitro et pour les analogues les plus actifs les DMT ont été déterminées in vivo. L'analyse détaillée des activités antibactérienne, antimycobactérienne et antiproliférative nous a permis de mettre en évidence quelques règles générales de relation structure-activité concernant l'influence du type de substitution du noyau quinolone, de la longueur de la chaîne alkyle et de la structure type dimère ou monomère sur les différentes cibles biologiques.Ciprofloxacin (CIP) and levofloxacin (LEV) are members of the large family of fluoroquinolone (FQ) antibiotics. Though they have proved to be reliable and effective antibacterial broad-spectrum agents, with several members also approved as second-line drugs for tuberculosis treatment. Nevertheless, the emerging resistance among key bacterial pathogens and M. tuberculosis hinders their future effectiveness. So there is a constant need for new compounds which could help to overcome these obstacles. In addition, studies have shown that LEV and CIP have antiproliferative and apoptotic activities against several cancer cell lines. The exact mechanism by which FQs exert their tumour growth inhibitory activity and lead to cell death is not fully understood but these molecules could inhibit mammalian topoisomerase II, G-quadruplexes and tubulin polymerization. Moreover, we reported that some 7-(4-substituted)piperazin-1-yl) derivatives of CIP with increased lipophilicity displayed increased antiproliferative activity in vitro, suggesting that grafting long alkyl chain could give rise to antitumor agents. During the course of the thesis, we have designed and synthesized five series of CIP and LEV derivatives. A number of optimization runs were conducted in order to overcome the low reactivity of C-3 carboxylic acid on quinolone core. The influence of various parameters was examined (microwave-assisted synthesis versus thermal conditions, presence or absence of catalyst), which permitted us to increase the yields and decrease the reaction time. Biological evaluation of these five series of FQ analogs was conducted in vitro together with in vivo MTD determination for the most potent ones. The detailed analysis of antimicrobial, antimycobacterial and antiproliferative activities permitted us to deduce general structure-activity relationships concerning the influence of substitution type on quinolone core, the length of the grafted alkyl chain and the ?dimeric? or ?monomeric? structure on the selectivity and potency against these various biological targets

Multiple Topoisomerase I (TopoI), Topoisomerase II (TopoII) and Tyrosyl-DNA Phosphodiesterase (TDP) inhibitors in the development of anticancer drugs

DNA Topoisomerases (Topos) are ubiquitous nuclear enzymes involved in regulating the topological state of DNA and, in eukaryotic organisms, Topos can be classified into two structurally and functionally different main classes: TopoI and TopoII. Both these enzymes proved to be excellent targets of clinically significant classes of anticancer drugs. Actually, TopoI or II inhibitors show considerable wide spectrum antitumor activities, an important feature to be included in many chemotherapeutic protocols. Despite their clinical efficacy, the use of inhibitors targeting only one of the two enzymes can increase the levels of the other one, favouring the onset of unwanted phenomena such as drug resistance. Therefore, targeting both TopoI and TopoII can reduce the probability of developing resistance, as well as side effects thanks to the use of lower doses, given the synergistic effect of the dual activity. Moreover, since drug resistance is also due to DNA repair systems such as tyrosyl-DNA phosphodiesterases I and II, inhibiting Topoisomerases concomitantly to Tyrosyl-DNA phosphodiesterase enzymes could allow more efficient and safe drugs. This review represents an update of previous works reporting about dual TopoI and TopoII inhibitors, but also an overview of the new strategy regarding the development of derivatives able to simultaneously inhibit Topo and TDP enzymes, with particular attention to structure-affinity relationship studies. The newly collected de-rivatives are described focusing attention on their chemical structures and their biological profiles. The final aim is to highlight the structural requirements necessary for the development of potent multiple modulators of these targets, thus providing new potential antitumor agents for the clinical usage

Insilico, Synthesis, Characterization and Biological Evaluation of Novel Isatin Analogues

INTRODUCTION:The branch of science concerned with the substance of which matter is composed, the investigation of their properties and reactions, and the use of such reactions to form new substances are called as chemistry. Chemistry is the central science because it bridges other natural sciences, including physics, geology and biology. The atom is the basic unit of chemistry. It consists of a dense core called atomic nucleus surrounded by a space called the electron cloud. The nucleus is made up of positively charged protons and uncharged neutrons, while the electron cloud consists of negatively charged electrons which orbit the nucleus. In a neutral atom, the negatively charged electrons balance out the positive charge of the protons. A chemical element is a pure substance which is composed of a single type of atom, characterized by its particular number of protons in the nuclei of its atoms, known as atomic number and represented by the symbol Z. The mass number is the sum of the number of protons and neutrons in a nucleus. Although all the nuclei of all atoms belonging to one element will have the same atomic number, they may not necessarily have the same mass number, atoms of an element which have different mass number are known as isotops. A pure chemical substance composed of more than one element is called as compound.RESEARCH OBJECTIVES:Nitogen atom containing analogues possess significant pharmacological activities. Various hetero cyclic nucleuses containing nitrogen as a hetero atom such as Indole, Imidazole, Benztriazole, Benzoxazole, Triazole, Tetrazole, and Benzimidazole possess varied pharmacological activities. Imidazole moiety is a versatile lead molecule. It is nitrogen containing heterocyclic ring which possess wide range of biological activities such as anti-bacterial, anti-cancer, anti-tubular, anti-fungal, analgesic and anti-HIV activities. Among, the various synthetic products, the first choice of selection of nucleus in our current research work are isatin. Isatin nucleus have attracted the attention of medicinal chemists due to their wide range of biological activities like as anti-microbial, anti-cancer, anti-convulsant activity and acts as a anxiogenic, sedative and potent antagonist on atrial natriuretic peptide receptors in In-vitro. Isatin derivatives reported exhibit interesting pharmacological activities. The work was planned to perform that isatin was substituted by benzylamine at C-3 position to produce Benzylimino-isatin. The Benzylimino-isatin was substituted by various secondary amines at N-1 position to produce Benzylimino-isatin Mannich bases, exhibits interesting pharmacological activities. The present study is aimed to carry out the synthesis of Benzyliminoisatin Mannich base derivatives. For newer derivatives, Benzylimino-isatin as lead molecule by combining several secondary amines followed by formaldehyde will be synthesized as per literature method. Then, structures will be assigned by FT-IR and 1H NMR analysis. Further, the compounds are evaluated for biological activities such as anti-cancer and anti-microbial activities. In this aim, our current research work was initiated.SUMMARY AND CONCLUSION:Our current research work deals with manually designed, library of compounds (IM1-20) bearing benzylimino-isatin scaffold that performed docking study with E.coli Quinol-Fumarate Reductase with Bound Inhibitor HQNO enzyme (1kf6) [PDB code 1kf6] using Molegro Virtual Docker Evaluation version (MVD 2013.6.0) the best compounds were selected based on their Moldock score in order to synthesis of benzylimino-isatin (IS1)([(3Z)- 3-(benzylimino)-1,3-dihydro-2H-indol-2-one)]) and benzylimino-isatin mannich base derivatives with isatin as a parent moiety. Benzylimino-isatin (IS1) ([(3Z)- 3-(benzylimino)-1,3-dihydro-2H-indol-2-one)]) and benzylimino-isatin mannich bases such as IM1 [(3Z)-3-(benzylimino)-1-[(dimethylamino) methyl]-1, 3- dihydro-2H-indol-2-one], IM3 [(3Z)-3-(benzylimino)-1-[(diphenylamino) methyl]-1, 3-dihydro-2H-indol-2-one], IM4 [(3Z)-3-(benzylimino)-1-[(piperazin- 1-yl methyl)-1, 3-dihydro-2H-indol-2-one], IM5 [(3Z)-3-(benzylimino)-1-[(4- methylpiperazin-1-yl) methyl]-1,3-dihydro-2H-indol-2-one], IM19 [(3Z)-3- (benzylimino)-1-[(morpholin-4-yl methyl)-1,3-dihydro-2H-indol-2-one] & IM20 [2-{[(3Z)-3-(benzylimino)2-oxo-2,3-dihydro-1H-indol-1yl)methyl]}-1H-isoindole- 1,3(2H)-dione] were synthesized by the suitable experimental procedure. The synthesized compounds were characterized by melting point, solubility and subjected to various common analytical techniques like TLC, FT-IR and 1H NMR and it is confirmed by means of their FT-IR and 1H NMR spectrum reports were in complete agreement with the chemical structure. The synthesized compounds were screened for in-vitro anti-microbial activity by disc diffusion method as well as well diffusion method and in-vitro anti-cancer activity by MTT assay method. Among the evaluated compound, three compounds such as IM3 [(3Z)-3-(benzylimino)-1-[(diphenylamino) methyl]-1, 3-dihydro-2H-indol-2-one], IM4 [(3Z)-3-(benzylimino)-1-[(piperazin- 1-yl methyl)-1, 3-dihydro-2H-indol-2-one] & IM20 [2-{[(3Z)-3-(benzylimino)2- oxo-2,3-dihydro-1H-indol-1yl)methyl]}-1H-isoindole-1,3(2H)-dione] have good in-vitro anti-microbial activity at a dose of 50 and 100 μg/0.1 mL, when compared to standard drug Ciprofloxacin at a dose of 10 μg/0.1 mL.Among the evaluated compounds, two compounds such as IM3 [(3Z)-3-(benzylimino)- 1-[(diphenylamino) methyl]-1, 3-dihydro-2H-indol-2-one] & IM20 2-{[(3Z)-3- (benzylimino)2-oxo-2,3-dihydro-1H-indol-1yl)methyl]}-1H-isoindole-1,3(2H)- dione have good in-vitro anti-cancer activity with IC50 0.392 μg/mL and 0.327 μg/mL aagainst human cervical cancer cell line (HeLa cell line) when compared to standard about 5FU with IC50 0.21 μg/mL. From the above facts it can be suggested that the benzylimino-isatin mannich base derivatives finds an interesting field of research because of their varied pharmacological activities