Mini-Reviews in Organic Chemistry - Volume 11, Issue 1, 2014

Infectious diseases are a significant cause of morbidity and mortality worldwide, accounting for approximately 50% of all deaths in tropical countries and as much as 20% of deaths in the USA. The emergence of multi-drug resistant (MDR) strains makes the risk of these infections even more threatening and an important public health problem thereby increasing need of new agents for fighting pathogens. In this review, the remarkable antibacterial properties possessed by various snake venoms (Crotalide, Elapidae, and Viperidae families) were discussed and in particular phospholipase A2s (PLA2s) that have emerged from various studies as potential in the last few years. Group IIA PLA2s are the most potent among the snake venom (sv)PLA2s against various types of bacteria. Further, antibacterial derivatives from PLA2s, e.g. peptides derived from the C-terminal sequence of Lys49-PLA2s (amino acids 115-129), kill bacteria and cause severe membrane-damaging effects. Mechanisms of binding to the bacterial surface and subsequent killing by peptides are based on positive charge, hydrophobicity, and length. These peptide candidates are easy to design and synthesize in pure form (~95% purity). Such peptides may be potentially useful in the clinic as new antimicrobials for combating infections due to antibiotic-resistant bacteria that include methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus in the near future.

The extensive use of antibiotics in medicine, food industry, and agriculture has led to a frequent emergence of multidrug-resistant bacteria, which creates an urgent need for new antibiotics. It is now widely recognized that venom proteins could play a promising role against multidrug-resistant bacteria. Different proteins with antibacterial activity have been characterized from the venoms of snakes, spiders and scorpions in the last decade. This review summarizes the proteins and peptides that have been purified and characterized from different venoms with antibacterial activity.

Snake venoms are rich sources of metalloproteinases that are of biological interest due to their diverse molecular diversity and selective therapeutic applications. Snake venoms metalloproteinases (SVMPs) belong to the MEROPS peptidase family M12B or reprolysin subfamily, which are consisted of four major domains include a reprolysin catalytic domain, a disintegrin domain, a reprolysin family propeptide domain and a cysteine-rich domain. The appropriate structural and massive sequences information have been available for SVMPs family of enzymes in the Protein Data Bank and National Center for Biotechnology Information, respectively. Functional essentiality of every domain and a crucial contribution of binding geometry, primary specificity site, and structural motifs have been studied in details, pointing the way for designing potential anti-coagulation, antitumor, anti-complementary and anti-inflammatory drugs or peptides. These enzymes have been reported to degrade fibrinogen, fibrin and collagens, and to prevent progression of clot formation. Angiotensin- converting enzyme activity, antibacterial properties, haemorrhagic activity and platelet aggregation response of SVMPs have been studied earlier. Structural information of these enzymes together with recombinant DNA technology would strongly promote the construction of many recombinant therapeutic peptides, particularly fibrinogenases and vaccines. We have comprehensively reviewed the structure-function-evolution relationships of SVMPs family proteins and their advances in the promising target models for structure-based inhibitors and peptides design. Moreover, structurefunction- evolution integrity of metalloproteinase from Gloydius halys venom was preliminarily analyzed herein that may provide a conceptual idea for the future of antibacterial peptide design.

It is a time tested phenomenon that in spite of deadly toxins in snake venoms, they are used for curing certain ailments of human suffering. Historically this application appears to co-evolve in many countries where India has significant contribution. Before independence, few British surgeons and naturalists documented the profile of snakes in India and investigated their venoms. With the advancement of technology, it is now conclusively known that venoms are rich source of bioactive compounds that can be used for therapeutic purposes. Many venom components have been purified and their structures at molecular level have been derived. Since overproduction of peptides and proteins are now possible in vitro, venom components are likely to serve as templates or scaffold to provide information for developing drugs of discrete specificity and high potency. Venom components are used as diagnostic tool, e.g. Russell’s viper (Daboia russelli) venom factor V and X activator and ecarin from Saw scaled viper (Echis carinatus) venom for blood clotting test. Components from cobra (Naja naja) venom showed good results as chemotherapeutic agent in the clinical trials. In this review, the trend of investigations on snake venom in India from ancient time to modern period has been presented focusing on their therapeutic applications.

The use of microwave energy in chemical reactions has revolutionized the field of heterocyclic chemistry in the past two decades. Synergy of microwave methodology with reactions performed on support media and/or in the absence of solvent constitutes an environmentally clean technique, that offers tremendous advantages such as clean chemistry, reduction in reaction times, improved yields, and applicability to wide range of reactions, safety and tremendous scope for automation over the traditional heating. The benzoannulated azaheterocycles display an impressive repertoire of biological activities. The present review will provide an in-depth view of microwave-assisted synthetic methodologies of benzo-fused seven-membered azaheterocycles such as benzodiazepines, benzothiazepines and benzoxazepines.

Spirocyclic scaffolds are embedded in many biologically active natural and synthetic compounds. Efforts have been made time to time to develop new and better methodologies for the preparation of spirocyclic compounds. Noteworthy advantages were observed during the course of our study on “in water” synthesis of spirocyclic compounds. The established advantages of using water as a solvent in reactions are: water is the most abundant and available resource on the planet and that many biochemical processes occur in aqueous medium. This review is focused on the use of water in the synthesis of spirocyclic compounds.

Catalytic asymmetric oxidation of prochiral sulfides has been a challenging goal for years, which reflects the importance of sulfinyl group as a chiral controller in many organic transformations, as well as the existence of natural and synthetic biologically active products that need a sulfinyl group with a defined stereoconfiguration. 30 years ago, owing to the milestone discoveries of Kagan and Modena, titanium-dialkyltartrate/alkyl hydroperoxide catalyst systems emerged as the protagonists in this area. In the last decade, various types of novel titanium based catalyst systems were developed, exploiting ‘green’ hydrogen peroxide as the terminal oxidant. This mini-review is aimed at discussing recent advances in enantioselective sulfoxidations with H2O2 in the presence of new generation chiral titanium catalysts, demonstrating high reactivity, efficiency, and enantioselectivity, which are likely to contribute to preparative syntheses of biologically active sulfoxides in near future. Peculiarities of their behavior and mechanisms of their catalytic action are discussed. Their viability is analyzed from the industrial and green chemistry perspectives.

The reflection of green chemistry for the synthesis of a wide range of compounds via multi-component reaction systems is discussed in this paper. It also describes the most interesting, atom-economic Mannich and Mannich type reactions, their processes via green methods, solvents, green solvents, solvent effects, catalysts, catalyst effects, selectivity, kinetics, etc. They are indeed environmentally and ecologically benign.