Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 16, Issue 1, 2017

Background: Leishmaniasis is a complex devastating disease that is widespread across the globe with 400 million people in 90 countries at a risk of acquiring leishmaniasis. It is caused by intracellular parasites belonging to genus Leishmania. Objective: The therapeutic use of commonly available drugs like Pentostam, Glucantime, Amphotericin B, Paramomycin, and Miltefosine have has been declined due to their low efficacy, drug resistance and high toxicity. Therefore, a continuous effort is needed in order to find out less toxic and more successful drugs in future for the handling of leishmaniasis. Results: Quinazoline derivatives are reported to have promising antileishmanial activities. A number of quinazoline derivatives were synthesized in the past three decades, by means of various synthetic pathways due to their ease of synthesis and favorable physicochemical properties. Conclusion: This review focuses on various synthetic procedures, chemical characteristics and antileishmanial activities of various quinazoline derivatives with respect to antileishmanial drug discovery.

Background: Antibodies constitute an important drug development platform for drugs to treat several ophthalmic, oncologic, and immunologic conditions, but due to limitations inherent in antibody production and structure, a wide range of other protein binding scaffolds are being investigated. Designed ankyrin repeat proteins (DARPins) are simple to produce and offer a range of advantages over antibodies because of their stability, high binding affinity, and rigid structure. Objective: DARPins are being developed for a wide variety of medical applications, and the most studied molecule, abicipar pegol, is used to treat chorioretinal vascular diseases. This mini-review will discuss the current state of DARPin technology and will summarize drug development with a focus on abicipar. Methods: PubMed searches with keywords “DARPin” and “designed ankyrin repeat proteins” were performed and the reference lists of identified articles were examined for additional research material. Studies using DARPin molecules were identified at Clinicaltrials. gov. Non-peer reviewed data were found through Google searches of pertinent websites. Results: Abicipar prevents angiogenesis by binding all isoforms of vascular endothelial growth factor (VEGF)-A with single-digit picomolar affinity. Abicipar has a long intraocular half-life in rabbits and has produced promising results in pre-clinical studies. Pivotal phase III registration trials for the treatment of neovascular age-related macular degeneration are ongoing and a phase II/III trial for the treatment of diabetic macular edema has been announced. Conclusion: Abicipar pegol has the potential to effectively treat chorioretinal vascular conditions with an extended duration of action beyond those of currently used anti-VEGF drugs.

Background: 2, 4-Thiazolidinedione (TZD), pyrazole and thiazole heterocyclic rings exhibit a wide range of pharmacological activities. Medicinal chemists use these heterocyclic moieties as scaffolds in drug designing and discovery. The existing medicaments, celecoxib and meloxicam, used for treating inflammation and pain are having, pyrazole and thiazole, respectively as key scaffolds. Pyrazoles coupled with 2, 4-thiazolidinediones may display enhanced anti-inflammatory activity. With this hope the bench work was carried out. Methods: Heterocyclic aldehydes, 3-(4-methyl-2-substituted thiazol-5-yl)-1-phenyl-1Hpyrazole- 4- carbaldehydes (4a-b) have been allowed to undergo Knoevenagel condensation with N-substituted 2,4-thiazolidinediones (5a-e) in PEG-400 in the presence of L-proline at 110°C and obtained the condensed products (6a-j). COX-2 evaluation of the titled product has been carried out using in vitro COX-2 ELISA Kit. Antibacterial activity of these compounds (6a-j) has also been determined. Results: On the basis of 1H NMR, 13C NMR and Mass spectral data of the condensed products the structures have been assigned to (Z)-5-((3-(4-methyl-2-substituted thiazol-5-yl)-1- phenyl-1H-pyrazol-4-yl)methylene) 3-substituted thiazolidine-2,4-diones (6a-j). Among the evaluated compounds (6a-j), 6f, 6g, 6h, 6i and 6j have shown notable COX-2 inhibitory activity. Conclusion: Compounds, 6a, 6b, 6c, 6d, 6e and 6f have inhibited the growth of the Bacillus cereus NCIM 2106, Bacillus subtilis NCIM 2063, Pseudomonas aeruginosa NCIM 2074, Salmonella typhimurium NCIM 2501 and Staphylococcus aureus NCIM 2079. However, compound 6f has emerged as a suitable candidate with dual properties i.e. COX-2 inhibitory and antibacterial in the present study.

Background: Phosphodiesterase 4 (PDE4), is one of the members of PDE superfamily which catalyzes the hydrolysis of cyclic adenosine monophosphate to adenosine monophosphate in pro-inflammatory and immunomodulatory cells, leading to increased inflammatory processes. PDE4 has been reported as an attractive therapeutic target involved in various inflammatory disorders. Objective: The present work was designed to synthesize and evaluate the anti-inflammatory activity of some new triazole amine derivatives as potential PDE4 inhibitors. Method: The present work involved the synthesis of a series of newer substituted triazole amine derivatives followed by characterization using FTIR and 1H-NMR spectroscopy and their in silico evaluation by docking studies to determine the binding interactions for the best fit conformations in the binding site of PDE4 protein. Based on the results of the in silico studies, the selected compounds were tested for the anti-inflammatory activity using carrageenan-induced paw oedema method. Results: The yields of synthesized compounds were moderate and amongst the synthesized molecules, compound 5 demonstrated high anti-inflammatory activity. The results of experimental studies were found to be in concordance with that of the in silico docking results. Most of the synthesized molecules were also found to possess drug like properties as contrived by Lipinski's rule of five. Conclusion: These newly synthesized molecules could act as the starting hits for the design of effective, potent and selective PDE4 inhibitors for the promising treatment of inflammatory disorders.