Combinatorial Chemistry & High Throughput Screening - Volume 19, Issue 7, 2016

A virtual screening analysis of our library of phytochemical structures with dengue virus protein targets has been carried out using a molecular docking approach. A total of 2194 plant-derived secondary metabolites have been docked. This molecule set comprised of 290 alkaloids (68 indole alkaloids, 153 isoquinoline alkaloids, 5 quinoline alkaloids, 13 piperidine alkaloids, 14 steroidal alkaloids, and 37 miscellaneous alkaloids), 678 terpenoids (47 monoterpenoids, 169 sesquiterpenoids, 265 diterpenoids, 81 steroids, and 96 triterpenoids), 20 aurones, 81 chalcones, 349 flavonoids, 120 isoflavonoids, 74 lignans, 58 stilbenoids, 169 miscellaneous polyphenolic compounds, 100 coumarins, 28 xanthones, 67 quinones, and 160 miscellaneous phytochemicals. Dengue virus protein targets examined included dengue virus protease (NS2B-NS3pro), helicase (NS3 helicase), methyltransferase (MTase), RNA-dependent RNA polymerase (RdRp), and the dengue virus envelope protein. Polyphenolic compounds, flavonoids, chalcones, and other phenolics were the most numerous of the strongly docking ligands for dengue virus protein targets.

Natural products are compounds extracted from plants, marine organisms, fungi or bacteria. Many researches for new drugs are based on these natural molecules, mainly by beneficial effects on health, health, efficacy, and therapeutic safety. Leishmaniosis, Chagas disease and African sleeping sickness are neglected diseases caused by the Leishmania and Trypanosoma ssp. parasites. These infections mainly affect population of developing countries; they have different symptoms, and may often lead to death. The therapeutic drugs available to treat these diseases are either obsolete, toxic, or have questionable efficacy, possibly through encountering resistance. Discovery of new, safe, effective, and affordable molecules is urgently needed. Natural organisms, as marine metabolites, alkaloids, flavonoids, steroids, terpene and coumarins provide innumerable molecules with the potential to treat these diseases. This study examines studies of natural bioactive compounds as antileishmanial and antitrypanosomal agents.

Neglected tropical diseases (NTDs) flourish mostly in impoverished developing nations of the world. It is estimated that NTDs plague up to 1 billion people every year thereby inducing a massive economic and health burden worldwide. Following explosive outbreaks mostly in Asia, Latin America, Europe and the Indian Ocean, two common NTDs namely, Chikungunya and Dengue both transmitted by an infected mosquito vector principally Aedes aegypti have emerged as a major public health threat. Given the limitations of conventional medicine in specifically targeting the Chikungunya and Dengue virus (CHIKV and DENV), natural products present an interesting avenue to explore in the quest of developing novel anti; mosquito, CHIKV and DENV agents. In this endeavor, a number of plant extracts, isolated phytochemicals, essential oils and seaweeds have shown promising larvicidal and insecticidal activity against some mosquito vectors as well as anti CHIKV and DENV activity invitro. Other natural products that have depicted good potential against these diseases include; the symbiotic bacterial genus Wolbachia which can largely reduce the life span and infectivity of mosquito vectors and the marine Cyanobacterium Trichodesmium erythraeum which has shown anti- CHIKV activity at minimal cytotoxic level. The impetus of modern drug discovery approaches such as high throughput screening, drug repositioning, synthesis and computer-aided drug design will undeniably enhance the process of developing more stable lead molecules from natural products which have shown promising antiviral activity in-vitro.

Mosquitoes (Diptera: Culicidae) are major vectors of important pathogens and parasites. Malaria, dengue fever, yellow fever, filariasis, schistosomiasis and Japanese encephalitis cause millions of deaths every year. Mosquito control is being challenging due to the development of pesticide resistance and negative environmental concerns. In this scenario, plants employed in traditional Asian medicine may be alternative sources of newer and effective mosquitocides. In this research, we evaluated the larvicidal activity of Kadsura heteroclita leaf essential oil (EO) and its major chemical constituents (δ-Cadinene, Calarene and δ-4-Carene) against the malaria vector Anopheles stephensi, the dengue vector Aedes aegypti and the filariasis vector Culex quinquefasciatus. The chemical composition of the EO was analyzed by gas chromatography–mass spectroscopy. GC-MS revealed that the essential oil of K. heteroclita contained 33 compounds. The major chemical components were δ-Cadinene (18.3%), Calarene (14.8%) and δ-4-Carene (12.5%). The EO had a significant toxic effect against early third-stage larvae of An. stephensi, Ae. aegypti and Cx. quinquefasciatus, with LC50 values of 102.86, 111.79 and 121.97 µg/mL. The three major constituents extracted from the K. heteroclita EO were tested individually for acute toxicity against larvae of the three mosquito vectors. δ-Cadinene, Calarene and δ-4-Carene appeared most effective against An. stephensi (LC50 = 8.23, 12.34 and 16.37 µg/mL, respectively) followed by Ae. aegypti (LC50 = 9.03, 13.33 and 17.91 µg/mL), and Cx. quinquefasciatus (LC50 = 9.86, 14.49 and 19.50 µg/mL). Overall, this study adds knowledge to develop newer and safer natural larvicides against malaria, dengue and filariasis mosquito.

Malaria parasites show resistance to most of the antimalarial drugs and hence developing antimalarials which can act on multitargets rather than a single target will be a promising strategy of drug design. Here we report a new approach by which virtual screening of 292 unique phytochemicals present in 72 traditionally important herbs is used for finding out inhibitors of plasmepsin-2 and falcipain-2 for antimalarial activity against P. falciparum. Initial screenings of the selected molecules by Random Forest algorithm model of Weka using the bioassay datasets AID 504850 and AID 2302 screened 120 out of the total 292 phytochemicals to be active against the targets. Toxtree scan cautioned 21 compounds to be either carcinogenic or mutagenic and were thus removed for further analysis. Out of the remaining 99 compounds, only 46 compounds offered drug-likeness as per the ‘rule of five’ criteria. Out of ten antimalarial drug targets, only two target proteins such as 3BPF and 3PNR of falcipain-2 and 1PFZ and 2BJU of plasmepsin-2 are selected as targets. The potential binding of the selected 46 compounds to the active sites of these four targets was analyzed using MOE software. The docked conformations and the interactions with the binding pocket residues of the target proteins were understood by ‘Ligplot’ analysis. It has been found that 8 compounds are dual inhibitors of falcipain-2 and plasmepsin-2, with the best binding energies. Compound 117 (6aR, 12aS)-12a-Hydroxy-9-methoxy-2,3-dimethylenedioxy-8-prenylrotenone (Usaratenoid C) present in the plant Millettia usaramensis showed maximum molecular docking score.

In this research, a general synthetic method for the synthesis of 3,4- dihydroquinoxalin-2-amine derivatives was developed using Co3O4@SiO2 nanoparticles under ultrasonic irradiation. Firstly by a simple and green process, Co3O4@SiO2 nanoparticles were prepared via sonication, and then these nanoparticles were used as an efficient catalyst for the synthesis of 3,4- dihydroquinoxalin-2-amines via three-component reactions of ophenylenediamines (OPDA), diverse ketones and various isocyanides in ethanol under ultrasound irradiation. The combinatorial synthesis was attained for this procedure with applying ultrasound irradiation while making use of ethanol as green ambient. The present approach offers several advantages such as high yields, environmentally benign, simple work-up, excellent yield of products and short reaction times. The nanomagnetic catalyst could be readily recovered using a simple external magnet and reused several times without any significant loss in activity. The catalyst was fully characterized by FT-IR, FE-SEM, XRD, EDX, VSM and TEM analysis.