Current Topics in Medicinal Chemistry - Volume 17, Issue 2, 2017

Cancer, the much dreaded name, is a multifactorial and genetically a difficult disease with less or so far no 100% cure available. Globally, it has become a major social concern and worsened the economical burden, with emergence of 1,658,370 new cancer cases and 589,430 cancer deaths in the United States only in 2015. In India, the scenario is no better with high cancer prevalence of around 2.5 million incidences, with over 800,000 new cases occurring each year. By 2015, WHO has predicted estimated deaths by cancer to be 700,000. The increase could be accounted to urbanization, industrialization, hectic and unhealthy lifestyle, increased life expectancy and population growth. The current treatment regimes are becoming inefficacious due to tumor heterogeneity and increased resistance to drugs. Bioactive compounds from natural resources have revolutionized the arena of drug chemistry and rapid researches in in vitro and in vivo studies are encouraging. These natural therapeutic agents have therefore, become important for the development of multi- treatment strategies to be deployed in cancer therapy. The review summarizes the various chemopreventive and bioactive compounds isolated from several herbs which have become milestone in various kinds of tumor treatments. Also emphasis is led on including latest research data obtained from animal cell culture, animal models and preclinical trials studies conducted by scientists around the world to derive potential anti-tumorigenic agents. Finally, the review examines mechanisms of action of these compounds which will add to our existing knowledge and effort to serve and enhance the current chemotherapeutic protocols.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the group of drugs prescribed in various pain related disorders and inflammatory conditions. Diclofenac (DI) is widely prescribed drug for chronic inflammatory conditions like osteoarthritis (OA), a highly prevalent musculoskeletal disorder of adults, projected to affect about 60 million people of total world population by 2020. The chronic oral administration of diclofenac is linked with many gastrointestinal complications like ulceration, bleeding and perforation. These issues paved the way for the development of a structurally similar drug Aceclofenac, which proved to be a safer and more efficient alternative. In spite of better tolerability of Aceclofenac, the oral use of it is not completely free from typical NSAID like side effects. Thus in this context, it becomes mandatory to explore the potential of newer delivery approaches. Amongst the varied newer carrier-systems, microemulsion systems, lipidic colloidal carrier systems and many other supramolecular systems promise to improve the delivery. They tend to place the molecules to the desired target site or in the vicinity without disturbing the unaffected normal surrounding tissues and also ensure enhanced permeation into the skin. The current investigation highlights and deals with the different conventional and novel approaches used thus far in oral delivery of Aceclofenac, their limitations and recent shift towards non oral routes.

Indole is a potential lead for drug design which has been found in numerous pharmaceutically important compounds due to its medicinal properties, such as anti-tumor, anti-bacterial, anti-virus and anti-inflammatory. In the last decade, interfering with microtubule polymerization, a potential orientation to cause cell cycle arrest and apoptosis has become a promising method for cancer therapy. Thus, indole-based agents capable to modulate the microtubule assembly have gained considerable interest among scientists. This review describes the synthesis, bioactivities and SARs of indole-based agents targeting tubulin polymerization during the past decade.

Structural polymorphism is an extremely significant phenomenon of nucleic acids, in which DNA and RNA oligonucleotide sequences are able to adapt various canonical, alternative and multistranded structures. These alternative forms of DNA and RNA have an enormous potential of participating in various cellular processes by recognizing ligands such as proteins, drugs and metal ions in a sequence and structure-specific manner. Such DNA-ligand interactions prove to be highly beneficial when exploited for therapeutic purposes. Many of these DNA/ RNA structures recognizing drugs have already proved their potential as anticancer, antibacterial, anthelmintic and antiviral properties. Over the last 2-3 decades, many mechanisms of DNA-drug interactions have been documented, but still many other new mechanisms are being explored. Designing new drugs with improved efficacy and specificity is of prime concern for all researchers which not only deals with the experiments related to synthesizing drugs, but also takes care of searching novel routes or agents for administration or delivery of these therapeutic agents by increasing their nuclear and cellular uptake. This review aims at explaining the structural polymorphs/ multistranded DNA structures and their interactions with pharmaceutical drugs in a structure-specific manner, along with their modes of interactions and biological relevance. This detailed overview of multistranded DNA structures and interacting drugs might further facilitate our understanding about molecular targets and drug development in a more precise manner for the larger benefit of mankind.

Curcumin, a natural yellow phenolic compound, is present in various types of herbs, particularly in Turmeric, Curcuma longa Linn. (Zingiberaceae family) rhizomes. Curcumin is a polyphenolic natural compound with diverse and attractive biological activities. In the last decade curcumine and its various synthetic analogues have been prepared and evaluated for various pharmacological activities that prove it as a lead molecule against several biological targets. It is a natural antioxidant and exhibited many pharmacological activities such as anti-inflammatory, anti-microbial, anticancer, anti-Alzheimer in both preclinical and clinical studies. Moreover, Curcumin and its analogues have anti-tubercular, cardioprotective, anti-diabetic, hepatoprotective, neuroprotective, nephroprotective, antirheumatic and anti-viral activities. The substitutions of 1,6-heptadiene linkage moiety via carbonyl group sustituion and addition of heterocyclic linker; isoxazole, 1H-pyrazole, cyclopentanone, piperidin-4-one, N-methylpiperidin-4-one enhance biological activities. The structure activity relationship of various curcumin analogues is studied for medicinal purposes and it reveals that monocarbonyl linkage analogues have anticancer properties. The current review gives an insight of the history, chemistry, analogues and most interesting in vitro and in vivo studies on the biological effects of Curcumin and its analogues.

There are several significant setbacks including limited bioavailability, high clearance, and further current therapies require higher and frequent dosing to gain desired therapeutic effects. Nanomedicines have been widely investigated for rheumatoid arthritis (RA). Though, higher doses also increase the incidence of dreadful adverse effects. Further, nanocarrier properties are tuned by the use of different approaches like varied methods of loading, hydrophilic polymers and targeting ligands, to change the physicochemical properties including higher encapsulation, better penetrating ability to biological barriers, thus preventing the uptake of various nanocarriers by liver and spleen. Along with these they provide longer circulation which enhances drug localization at the inflamed site and selective targeting to enhance the therapeutic index of anti-rheumatic drugs. However, the optimal properties also depend on the route of administration and nanocarrier size, thus larger size show more retention upon local injection and smaller sized ones are more optimal for passive targeting. The present review discusses the emergence of nano-carriers for anti-rheumatic drugs, which delivers drug molecule to the inflamed site by topical, intra-articular (i.a) and intra-venous (i.v) administration to achieve therapeutic efficacy by passive and active drug targeting. Advancements have been made extensively but still better investigations are needed to optimize the risk-benefit ratio for the development of safe and stable targeting nanocarriers for the effective treatment of rheumatoid arthritis (RA).

Recently, noscapine was reported as anticancer drug. Unlike, colchicine and podophyllotoxin, noscapine did not depolymerize microtubules even at stoichiometric concentrations but rather only mitigated their dynamics. Other microtubule-interacting chemotherapeutics, although quite effective, have therapy-limiting toxicities including immunosuppression and peripheral neuropathies. Recurrent cancers often become resistant. Noscapine however remains effective in some such instances, e.g., taxane-resistant ovarian cancer. Noscapine and analogs also do not show signs of neurotoxicity or immunosuppression. In addition, 9-bromo noscapine, Red-9-Br-Nos and other analogs were characterized for their structure and further studied in detail. On the other hand, noscapine was shown to be neuroprotective in mouse model of neurodegenerative disease and in stroke patients. Like low doses of colchicine, noscapine and its analog 9-Br-Noscapine also show anti-inflammatory activities. There are indications of a preventive use of noscapine in ischemiareperfusion injury and fibrosis. The entire biosynthetic pathway of noscapine is encoded as gene cluster within 401 kilo bases of genomic DNA, opening up opportunities for the large-scale biotechnological production of noscapine for medicinal needs. Thus, noscapine and its derivatives (noscapinoids) might be cost-effective and safe components for cancer chemotherapy. Owing to its low toxicity, it also might be useful for preventive use in high-risk situations. This brief review is an update of current research activity and patents on noscapine and its analogs.

Isoindole derivatives constitute an important class of biologically active heterocyclic compounds and continue to attract considerable attention due to their diverse pharmacological profile such as, antimicrobial, anthelmintic, insecticidal, cyclooxygenase isoenzyme (COX-2) and thrombin inhibition with special emphasis on anticancer activity. This review highlights anticancer properties of isoindole derivatives and its related structures and hoping that it would further help in generation of new concepts towards rational design and development of more potent and less toxic anticancer agents.

Background: Severity of microbial infections and escalating resistance towards antibiotics has created a deep necessity for discovery of novel anti-infective agents. Heterocyclic chemistry of benzothiazole has become one of the most prolific areas in the field of drug discovery and development that has attracted great attention in recent time due to its increasing importance in the field of pharmaceuticals. Method: The importance of benzothiazole and derivatives as potential antimicrobial agents has been well established and a large number of papers have been published in this regard. Result: The present communication is an earnest attempt to review the chemistry, synthetic aspects including click chemistry and antimicrobial activities of benzothiazole derivatives reported in recent scientific literature. Conclusion: The scientific information of this manuscript may be worthwhile in encouraging the prospective researchers working on this heterocyclic scaffold.

Imidazo[1,2-a]pyridine is one of the most potential bicyclic 5–6 heterocyclic rings that is recognized as a “drug prejudice” scaffold due to its broad range of applications in medicinal chemistry such as anticancer, antimycobacterial, antileishmanial, anticonvulsant, antimicrobial, antiviral, antidiabetic, proton pump inhibitor, insecticidal activities. This scaffold has also been represented in various marketed preparations such as zolimidine, zolpidem, alpidem. Therefore, several attempts were made to carry out the structural modifications of this scaffold to discover and develop novel therapeutic agents. This review provides a valuable insight into the research findings of wide range of derivatives of imidazo[1,2-a]pyridine scaffold leading to promising heterocyclic compounds which could be explored further for the synthesis of new derivatives as well as construction of potential drug-like chemical libraries for biological screening in search of new therapeutic agents.

Antibiotics are wonder drugs. Unfortunately, owing to overuse, antibiotic resistance is now a serious problem. Society now finds itself in the post-antibiotic era, and the threat of infectious diseases is on the rise. New antibiotics are sorely needed. There is strong evidence that suggests natural products are an attractive source of new antimicrobials. They posses desirable structural and chemical properties that make them potent thearpeutics. However, steep tehnological challenges associated with screening and manufacturing these molecules has stifled the discovery, development and marketing of new antimicrobials. To this end, two recent scientific developments are poised to redress this situation. The recent development of metagenomics and ancillary high-throughput screening technologies has exponentiated the volume of useful genetic sequence information that can be screened for antimicrobial discovery. These approaches have been instrumental in the discovery of new antibiotics from soil and marine environments. Secondly, a new manufacturing paradigm employing metabolic engineering as its engine has greatly accelerated the path to market for these molecules, in addition to improving the atom and energy economy of antimicrobial manufacturing. We outine these developments in this review, and provide a perspective on integrating next-generation approaches such as metagenomics and metabolic engineering with traditional methodologies for discovering and manufacturing antimicrobial natural products in order to unleash a rennaissance in the discovery and development of antimicrobials.