Current Topics in Medicinal Chemistry - Volume 17, Issue 8, 2017

Andrographis paniculata (A. paniculata) is a medicinal plant used in the Indian and Chinese traditional medicinal systems for its various beneficial properties of therapeutics. This is due to the presence of a diterpene lactone called ‘andrographolide’. Several biological activities like antiinflammatory, antitumour, anti-hyperglycaemic, anti-fertility, antiviral, cardio protective and hepatoprotective properties are attributed to andrographolide and its natural analogs. The studies have shown that not only this diterpene lactone (andrographolide), but also other related terpenoid analogs from A. paniculata could be exploited for disease prevention due to their structural similarity with diverse pharmacological activities. Several scientific groups are trying to unveil the underlying mechanisms involved in these biological actions brough aout by andrographolide and its analogs. This review aims at giving an overview on the therapeutical and/or pharmacological activities of andrographolide and its derivatives and also exemplify the underlying mechanisms involved.

The multifunctional ligands application is an emerging approach in drug delivery, mainly in the treatment of diseases with complex pathology, such as Alzheimer’s, cancer, and epilepsy. Using this method many biomolecules with different properties are combined to form a single unit that can provide a complex broad spectrum activity. Thus, a new type of hybrid anticonvulsants based on the pyrrolidine-2,5-dione frame are detailed with the aim of acquiring more effective antiepileptic drugs (AED) that could suppress various human convulsions. These hybrid molecules attach to the chemical particles of clinically relevant AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result of this hybridization process the compounds obtained were effective in three most important animal epilepsy models, namely the maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-Hertz (6 Hz) model in mice. These substances displayed wider spectrum of protection, more potent efficacy, and better safety profile than the aforementioned AEDs. Several compounds were also active in the formalin model of persistent pain in mice. The in vitro ligand binding studies have proved that the most conceivable molecular mechanism of anticonvulsant and antinociceptive action was the influence on the neuronal voltage-sensitive sodium and L-type calcium channels.

The search for a miracle drug that would help to alleviate multiple ailments, dates back many thousands of years before our era and continues until today. Various techniques have been used to obtain a formulation, that would give the desired therapeutic effect. The most popular approach includes drug coctails and multicomponent drugs. Polytherapy is widely accapted as an effective tool for the treatment of several diseases, however it is often faced with important drawbacks that may sometimes result in fatal adverse effects associated with unpredictable drug interactions. Conversly, hybrid compounds were found to be an attractive way to counterbalance the unwanted side effects derived from the administration of individual drug components. Futhermore, they can serve as effective and improved remedies for patients suffering from several diseases simultaneously, as different receptorrelated pharmacophores are used as structural components. This review covers patent literature from 1980 till now that highlights the progress that has been made in the discovery of hybrid compounds potentially useful in the treatment on various disorders, including pain states, neurodegenerative or infectious diseases. Additionally, this review was further enriched with findings from original research papers.

Antimicrobial resistance to drugs is a serious threat to public health. Different strategies have been adopted to deal with antimicrobial resistance to known drugs, one such strategy is the use of drug hybrids; this is a promising strategy to address the growing problem of drug resistance. The present review covers the very recent examples of combining (hybrid) two standard drugs in a single molecule for combating antibiotic-resistant microorganisms, and to present evidence supporting that drug hybrids are the urgent and practical solution to stop or slow down the spread of drug resistance. In addition, this review provides a literature overview of antimicrobial hybrids of standard drugs and their impact on antimicrobial resistance, covering publications between 2015 and 2016.

Cancer is a multifactorial disease including interactions of complex genetic and environmental factors. Clinical efficacy of anticancer chemotherapies is hampered by various factors including multidrug resistance (MDR). There is a strong need to discover more potent novel cancer drugs to kill cancer cells selectively. The recent new strategy for cancer treatment involves the design and synthesis of hybrid compounds as multitargeted anticancer agents. In this review, we focus on studies using hybrid compounds which were designed and synthesized from two or more different bioactive moieties conjugating them into a single hybrid drug. Hybrid compounds having more than a single target have been considered as more efficient and potent anticancer agents, since it is almost impossible to destroy cancer cells with a single target. Hybrid compounds overcome many disadvantages of single cancer drugs such as low solubility, adverse effects, and multi drug resistance. We have compiled the data of recent studies using the new hybrid anticancer drugs in cancer treatment. Thus, the design, synthesis and clinical trials of new hybrid compounds should be continued and supported in future. Results of recent studies have proved that they have a great potential to be used as novel anticancer drugs.

Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encouraging developmental potential. Anti-inflammatory hybrids were obtained by combining macrolides with corticosteroid and non-steroidal anti-inflammatory drugs. They were found active in in vivo animal models of locally induced inflammation, asthma, inflammatory bowel disease and rheumatoid arthritis and demonstrated improved safety over parent steroid drugs. Overall, macrolide hybrids possess significant potential to be developed as potent novel medicines in therapeutic areas of utmost pharmaceutical interest.

Selective inhibition of cyclooxygenase-2 (COX-2) isozyme afforded a useful drug design concept that resulted in the development of effective anti-inflammatory drugs that are devoid of adverse side effects, in particular gastrointestinal irritation, ulcerogenicity and renal toxicity attributed to inhibition of the cytoprotective cyclooxygenase-1 (COX-1) isozyme. Unfortunately, some selective COX-2 inhibitory drugs such as rofecoxib and valdecoxib are believed to be responsible for cardiovascular complications. Nitric oxide (NO) is an effective vasodilator that also inhibits platelet aggregation. Therefore hybrid NSAIDs containing NO-donor moieties have been developed to obtain effective treatment of inflammation with reduced GI and cardiovascular side effects. Here we review some of the most promising recent advances in NO-NAISDs donor drug development and summarizes medicinal chemistry efforts in search for new NO-NSAIDs prodrugs in an attempt to pave the way for further development in this promising area of research.