Anti-Infective Agents - Volume 15, Issue 2, 2017

TB is one of the major infectious diseases caused by Mycobacterium tuberculosis (M.TB) with millions of people dying every year. Emergence of new cases, increased incidence of multi drug resistant strains of M.TB and the adverse effects of first and second line antitubercular drugs have led to renewed interest in natural products with the hope of discovering new antitubercular leads. Coumarins and chalcones are plant derived secondary metabolites with potentially exploitable activities against M.TB. To pave way for future antitubercular research, there is an urgent need to collect latest information on these promising moieties. The objective of this review is to focus on the newer and important coumarin and chalcone derivatives having potent antitubercular activity. General scheme of synthesis of coumarins and chalcones is presented. This review enlightens the landscape of the discovery and development of chalcones and coumarin based antitubercular drugs with an emphasis on Structure- Activity Relationship (SAR) and inhibition of some their specific molecular targets. We hope that this review paper would provide new opportunities for researchers to design future generation novel and potent coumarin and chalcone based antitubercular drugs with higher activity and lesser toxicity.

Background: The reign of allergic infections caused by pathogenic fungi during the past few decades has created a major concern among healthcare professionals. Fungal allergens cause allergic manifestations in atopic and healthy individuals as well. The presence of T-cell and B-cell epitopes is essential for a protein to be an allergen and sharing of these epitopes make the allergens cross reactive that is a major issue which should be considered while selecting fungus specific allergens for clinical and diagnostic applications. Methods: The present study is a gathered effort to provide the comprehensive analysis of the availa-ble fungal allergens for presence of T-cell and B-cell epitopes along with the hint of cross reactivity among allergens of different fungi. The annotation for about 1927 unique allergen sequences, related to 194 different fungal genus is compiled and made available freely to be used by researchers worldwide through internet from the url: http://facrd.mdurtk.in/. Besides this we have also put a step forward to de-velop SVM based classifiers trained on reported fungal allergens and capable of making in silico predic-tions of novel allergens. Result: The classifiers are provided in the download section of the web pages for the interested users. Conclusion: The main purpose of this study is to help with the better management of fungal aller-gies by predicting novel allergens as well as cross reactivity among them.

Background: Microemulsion is one of the promising sub-micron carriers for topical drug delivery as it offers advantages like high drug-loading capacity and good skin penetration. Microemulsion based gel of voriconazole (broad-spectrum antifungal agent) could be an effective strategy for treatment of topical fungal infections. Objective: To develop microemulsion based hydrogel of voriconazole was for effective treatment of skin mycosis. Methods: Optimized microemulsion batches were selected through pseudoternary phase diagram (using oleic acid, tween 80 and IPA as oil, surfactant and co-surfactant, respectively) followed by stability studies and characterization. Results: The drug content and pH were found in the desired range. The droplet size of optimized formulations were found within the desired range (<200nm). The hydrogel prepared (from selected microemulsion batches) were found to have good spreadability and texture (adequate adherence). The in-vitro and ex-vivo studies exhibited effective VCZ flux from microemulsion based gel. The skin retention of the drug from F12-Me-Gel was significantly higher when compared with the microemulsion (F12-ME) as well as the conventional gel. Similarly, the diameter of the zone of inhibition (against Candida albicans) of F12-Me-Gel found to be higher than the microemulsion batch (F12-ME). Moreover, the skin irritation studies confirmed the benignity of the microemulsion based gel. Furthermore, the formulation was found to be stable at various temperatures (5 ± 3, 25 ± 2 and 40 ± 2 °C) as reported by the stability studies. Conclusion: Voriconazole loaded microemulsion based gel could be used effectively for the treatment of topical fungal infections.

Background: The large scale growing and harvesting of Calamus aromaticus, a medicinally important weed, is rampant in Asia due to its well-known medicinal importance. The gigantic antimicrobial potential of C. aromaticus, however, is not reflected in the absolute sense by the efforts devoted to this purpose so far. Methods: The role of Gallic acid in the determination of antibacterial potency was established by first assessing the biological activity of different solvent extracted samples from the commercially available rhizome of C. aromaticus through disc diffusion assay. The different extracts were then quantified for the presence of Gallic acid using HPLC. Results: Staphylococcus aureus and Citrobacter freundii were more susceptible to crude methanol extract at 2000 μg.disc-1 (31.6% and 32.1% respectively) while Bacillus subtilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli and Xanthomonas campestris were more susceptible to ethyl acetate fraction at the same concentration (40.6%, 31.5%, 39.8%, 41.7% and 48.3% respectively). S. aureus was most susceptible gram positive bacterium and B. subtilis was comparatively more resistant. Among Gram negative bacteria, P. aeruginosa showed maximum susceptibility while K. pneumoniae revealed more resistivity in comparison to others. HPLC analysis of the extracts confirmed the hypothesis about the role of Gallic acid, with ethyl acetate fraction revealing the highest amount of the phenolic (12.6 mg.g-1). Conclusions: Organic solvents were found to be the solvents of choice for the extraction of Gallic acid and the results also pointed towards the potential of Gallic acid as a broad spectrum antibacterial agent.

Background: Glycoprotein120 (GP120) is an emerging target nowadays to design novel human immunodeficiency virus-1 (HIV-1) entry inhibitors. It plays a crucial role in the first stage of viral attachment through binding to CD4 receptors of host cell but currently there is no approved drug in the market targeting this HIV-1 GP120. Thus, there is an urge of novel lead molecules as GP120-CD4 binding inhibitors. Methods: To design such novel molecules, 3D-QSAR studies were performed on a series of 48 reported indole glyoxamide derivatives using two different alignment methods. Best significant CoMFA and CoMSIA models were obtained using 35 molecules in training set by distill alignment. Results: CoMFA model gave 0.698 cross-validated coefficient (q2) and 0.921 conventional coefficient (r2) while CoMSIA outperformed with 0.732 q2 and 0.946 r2. Validation of both the models using 13 molecules test set resulted in satisfactory predicted correlation coefficient (r2 pred) values of 0.625 and 0.761 for CoMFA and CoMSIA, respectively. Conclusion: Interpretation of CoMFA and CoMSIA contour maps along with the docking results of all 48 compounds into a Phe43 cavity of GP120 revealed many helpful structural insights to improve the activity of newly designed indole glyoxamide derivatives as GP120-CD4 inhibitors for the treatment of HIV-1 infection.

Background: Heterocyclic compounds have attracted much attention to synthetic and medicinal chemists because of their biological activities especially for tuberculosis (TB).Moreover, fatal forms of TB (including tuberculous meningitis) have led to search for new structural anti-TB agents. So, we have built a scaffold using imidazo[1,2-b]pyridazine, piperazine and morpholine moieties, which are widely used in the inhibition of resistant strains of various organisms. Objective: The aim was to synthesise 6-morpholino-3-(piperazine-1-yl)imidazo[1,2-b]pyridazine containing amide and sulphonamide derivatives and evaluate their antimycobacterial and locomotor activities. Methods: The novel imidazo[1,2-b]pyridazine, piperazine and morpholine scaffolds have been synthesized in seven steps. All the synthesized compounds (8a-j) were screened for in vitro antimycobacterial activity against M.tb H37Rv strains using the MABA, in vivo locomotor activity by using photoactometer and rotarod apparatus. Results: All the synthesized imidazo[1,2-b]pyridazine analogues were characterized by 1H NMR, 13C NMR and ESI-MS. The compounds 8h and 8j exhibited potent in vitro anti-TB activity at 1.6 μg/mL concentration. Based on the structural and in vitro studies, we had related SAR of 8a-j. Overall, the amide derivatives showed better antitubercular activity than sulphonamide derivatives, which might be due to easy hydrogen bond formation. Moreover, all the derivatives showed significant CNS depressant action lacking neurotoxicity that indicates that the compounds 8a-j have strong lipophilic nature. Conclusion: The presence of novel structure, lipophilicity and non-toxic nature provide impetus for compounds 8a-j in the diagnosis of TB and tuberculous meningitis along with first line anti-TB drugs.