Antidiatom activity of marine bacteria associated with sponges from San Juan Island,Washington

Crude extracts of 52 marine bacteria associated with sponges, which were collected from the sea near San Juan Island, Washington, USA, were screened using diatom attachment assays against Amphora sp., Nitzschia closterium, Sellaphora sp. and Stauroneis sp. to investigate their antidiatom activities. Among these samples, five expressed strong anti-adhesion effects on all four tested diatoms. There was no negative effect observed from those five active samples on the growth of Amphora sp. Those five active samples were prepared from respective isolates, which all belonged to the genus Bacillus based on 16S rRNA gene sequencing analysis. The results of present study indicate that Bacillus may play important roles for sponges’ chemical defence against biofouling of diatoms and that the metabolites of Bacillus may be a potential source of natural antifouling compounds.     

Novel isoniazid embedded triazole derivatives: Synthesis,antitubercular and antimicrobial activity evaluation

In the present study, a series of new isoniazid embedded triazole derivatives have been synthesized. These compounds were evaluated for their in vitro antitubercular and antimicrobial activities. Among the screened compounds, six have exhibited potent antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC value 0.78 μg/mL, whereas, three compounds have displayed activity with MIC value ranging from 1.56 to 3.125 μg/mL. The cytotoxicity of the active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed even at 25 μg/mL concentration. The five compounds have displayed good antimicrobial activities. Molecular docking have been performed against mycobacterial InhA enzyme to gain an insight into the plausible mechanism of action which could pave the way for our endeavor to identify potent antitubercular candidates. We believe that further optimization of these molecules may lead to potent antitubercular agents.     

Bioactive potential of Streptomyces associated with marine sponges

The present work deals with isolation of Streptomyces associated with marine sponges and its bioactive potential. Streptomyces sp. were isolated from the marine sponges Callyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis. From the initial screening, 94 cultures of Streptomyces were obtained and from these 58 cultures exhibited antagonism against bacteria, 36 strains against fungi and 27 strains exhibited broad spectrum activity against both. The submerged culture extracts of the 58 anti-bacterial isolates were analysed and of these 58 strains, 37 strains showed positive inhibition against Bacillus subtilis, 43 against Staphylococcus aureus, 10 against Vibrio cholerae and 10 against Escherichia coli. The antifungal activities of the 36 strains were also evaluated and 27 strains showed positive inhibition against Aspergillus niger, 23 against Saccharomyces cerevisiae and 16 against Candida albicans. The production of polyene substances from the active extracts was confirmed by UV spectral analysis by the absorbance peaks that ranged from 225 to 262 nm and the TLC (R _f values) ranging from 0.40 to 0.78. The results indicate that Streptomyces strains isolated from marine sponges produce potential antibacterial, antifungal and broad spectrum antibiotic compounds.     

Synthesis and biological evaluation of new heterocyclic quinolinones as anti-parasite and anti-HIV drug candidates

We have synthesized quinolinones with potential antiparasitic and anti-HIV activities by an original two-step method involving microwave irradiation and have evaluated their activities against Plasmodium falciparum, Leishmania donovani, Trichomonas vaginalis, and HIV. None of the tested compounds had been previously described using this method of synthesis. One of the compounds had interesting antiparasitic and anti-HIV activity, which could be improved by substitution with different radicals.     

New amide linked dimeric 1,2,3-triazoles bearing aryloxy scaffolds as a potent antiproliferative agents and EGFR tyrosine kinase phosphorylation inhibitors

A search for potent antiproliferative agents has prompted to design and synthesize aryloxy bridged and amide linked dimeric 1,2,3-triazoles (7a–j) by using 1,3-dipolar cycloaddition reaction between 2-azido-N-phenylacetamides (4a–e) and bis(prop-2-yn-1-yloxy)benzenes (6a–b) via copper (I)-catalyzed click chemistry approach with good to excellent yields. All the newly synthesized compounds have been screened for their in vitro antiproliferative activities against two human cancer cell lines. The compounds 7d, 7e, 7h, 7i and 7j have revealed promising antiproliferative activity against human breast cancer cell line (MCF-7), whereas, the compounds 7a, 7b, 7c, 7i and 7j were observed as potent antiproliferative agents against human lung cancer cell line (A-549). The active compounds against MCF-7 have been also analysed for their mechanism of action by the enzymatic study, which shows that the compounds 7d, 7h and 7j were acts as active EGFR tyrosine kinase phosphorylation inhibitors. In support to this biological study, the molecular docking as well as in silico ADME properties of all the newly synthesized hybrids were predicted.     

Assessing the diversity of bacterial communities from marine sponges and their bioactive compounds

Symbiotic bacteria play vital roles in the survival and health of marine sponges. Sponges harbor rich, diverse and species-specific microbial communities. Symbiotic marine bacteria have increasingly been reported as promising source of bioactive compounds. A culturomics-based study was undertaken to study the diversity of bacteria from marine sponges and their antimicrobial potential. We have collected three sponge samples i.e. Acanthaster carteri, Rhytisma fulvum (soft coral) and Haliclona caerulea from north region (Obhur) of Red Sea, Jeddah Saudi Arabia. Total of 144 bacterial strains were isolated from three marine sponges using culture dependent method. Screening of isolated strains showed only 37 (26%) isolates as antagonists against oomycetes pathogens (P. ultimum and P. capsici). Among 37 antagonistic bacteria, only 19 bacterial strains exhibited antibacterial activity against human pathogens (Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 8739, Enterococcus faecalis ATCC 29212). Four major classes of bacteria i.e γ-Proteobacteria, α-Proteobacteria, Firmicutes and Actinobacteria were recorded from three marine sponges where γ-Proteobacteria was dominant class. One potential bacterial strain Halomonas sp. EA423 was selected for identification of bioactive metabolites using GC and LC-MS analyses. Bioactive compounds Sulfamerazine, Metronidazole-OH and Ibuprofen are detected from culture extract of strain Halomonas sp. EA423. Overall, this study gives insight into composition and diversity of antagonistic bacterial community of marine sponges and coral from Red Sea and presence of active metabolites from potential strain. Our results showed that these diverse and potential bacterial communities further need to be studied to exploit their biotechnological significance.     

Effects of marine organisms extracts on microtubule integrity and cell cycle progression in cultured cells

Marine organisms have been reported to be a rich source of biologically active compounds, but when compared with plants, their use is much more restrict in popular medicine. Among marine animals, sponges and ascidians are two of the most prominent sources of new compounds with cytotoxic potential. In this study, we tested 40 extracts of marine sponges and ascidians from southeastern Brazilian coast aiming to evaluate their anti-proliferative effects on cultured cells. The extracts of Amorphinopsis sp., Arenosclera brasilensis, Cystodytes dellechiajei, Cliona aff. celata, Didemnum sp., Hadromerida and Scopalina ruetzleri showed an IC₅₀≤30 μg/mL and produce strong effects on microtubules organization and on the cell cycle progression.     

Quinoxaline derivatives as potential antitrypanosomal and antileishmanial agents

Continuous efforts have been made to discover new drugs for the treatment of Chagas’ disease, human African trypanosomiasis, and leishmaniasis. We have previously reported the synthesis and antileishmanial and antitrypanosomal (Y strain) properties of 2,3-disubstituted quinoxalines. Considering their promising antiparasitic potential, the present study was conducted to expand our search and take advantage of high-throughput assays to investigate the effects of quinoxaline derivatives against Leishmania donovani, Trypanosoma brucei, and Trypanosoma cruzi (Tulahuen strain). These compounds were active against the kinetoplastid parasites that were evaluated. The 2-chloro-3-methylsulfoxylsulfonyl and 2-chloro-3-methylsulfinyl quinoxalines were the most potent, and some of these derivatives were even more active than the reference drugs. Although the 2,3-diaryl-substituted quinoxalines were not active against all of the parasites, they were active against T. brucei and intracellular amastigotes of T. cruzi, without interfering with mammalian cell viability. These compounds presented encouraging results that will guide our future studies on in vivo bioassays towards the mode of action.     

Screening for antibacterial and antifungal activities in marine benthic invertebrates from northern Norway

Benthic marine invertebrates collected from sub-Arctic regions of northern Norway, were found to be a promising source of novel bioactive compounds against human and fish pathogenic bacteria and fungi. Lyophilized material from seven species of ascidians, six sponges and one soft alcyonid coral were extracted with 60% acidified acetonitrile (ACN). After separation into an ACN-rich phase (ACN-extract) and an aqueous phase, and subsequent solid-phase extraction of the aqueous phase, fractions differing in polarity were obtained and screened for antibacterial and antifungal activities, along with the more lipophilic ACN-extracts. Antimicrobial activity was determined against two Gram-negative, two Gram-positive bacteria, and two strains of fungi. Notably, all the invertebrate species in the study showed activity against all four strains of bacteria and the two strains of fungi. In general, the aqueous fractions displayed highest antimicrobial activity, and the most potent extracts were obtained from the colonial ascidian Synoicum pulmonaria which displayed activity against bacteria and fungi at a concentration of 0.02 mg/ml; the lowest concentration tested.     

Screening of the Antarctic marine sponges (Porifera) as a source of bioactive compounds

Sponges (Porifera) currently represent one of the richest sources of natural products and account for almost half of the pharmacologically active compounds of marine origin. However, to date very little is known about the pharmacological potential of the sponges from polar regions. In this work we report on screening of ethanolic extracts from 24 Antarctic marine sponges for different biological activities. The extracts were tested for cytotoxic effects against normal and transformed cell lines, red blood cells, and algae, for modulation of the activities of selected physiologically important enzymes (acetylcholinesterase, butyrylcholinesterase, and α-amylase), and for inhibition of growth of pathogenic and ecologically relevant bacteria and fungi. An extract from Tedania (Tedaniopsis) oxeata was selectively cytotoxic against the cancer cell lines and showed growth inhibition of all of the tested ecologically relevant and potentially pathogenic fungal isolates. The sponge extracts from Isodictya erinacea and Kirkpatrickia variolosa inhibited the activities of the cholinesterase enzymes, while the sponge extracts from Isodictya lankesteri and Inflatella belli reduced the activity of α-amylase. Several sponge extracts inhibited the growth of multiresistant pathogenic bacterial isolates of different origins, including extended-spectrum beta-lactamase and carbapenem-resistant strains, while sponge extracts from K. variolosa and Myxilla (Myxilla) mollis were active against a human methicillin-resistant Staphylococcus aureus strain. We conclude that Antarctic marine sponges represent a valuable source of biologically active compounds with pharmacological potential.     

Diversity of cultivable fungi associated with Antarctic marine sponges and screening for their antimicrobial, antitumoral and antioxidant potential

The diversity of sponge-associated fungi has been poorly investigated in remote geographical areas like Antarctica. In this study, 101 phenotypically different fungal isolates were obtained from 11 sponge samples collected in King George Island, Antarctica. The analysis of ITS sequences revealed that they belong to the phylum Ascomycota. Sixty-five isolates belong to the genera Geomyces, Penicillium, Epicoccum, Pseudeurotium, Thelebolus, Cladosporium, Aspergillus, Aureobasidium, Phoma, and Trichocladium but 36 isolates could not be identified at genus level. In order to estimate the potential of these isolates as producers of interesting bioactivities, antimicrobial, antitumoral and antioxidant activities of fungal culture extracts were assayed. Around 51 % of the extracts, mainly from the genus Geomyces and non identified relatives, showed antimicrobial activity against some of the bacteria tested. On the other hand, around 42 % of the extracts showed potent antitumoral activity, Geomyces sp. having the best performance. Finally, the potential of the isolated fungi as producers of antioxidant activity seems to be moderate. Our results suggest that fungi associated with Antarctic sponges, particularly Geomyces, would be valuable sources of antimicrobial and antitumoral compounds. To our knowledge, this is the first report describing the biodiversity and the metabolic potential of fungi associated with Antarctic marine sponges.     

Allicin and derivates are cysteine protease inhibitors with antiparasitic activity

Allicin and derivatives thereof inhibit the CAC1 cysteine proteases falcipain 2, rhodesain, cathepsin B and L in the low micromolar range. The structure–activity relationship revealed that only derivatives with primary carbon atom in vicinity to the thiosulfinate sulfur atom attacked by the active-site Cys residue are active against the target enzymes. Some compounds also show potent antiparasitic activity against Plasmodium falciparum and Trypanosoma brucei brucei.     

Triphenylmethane Derivatives Have High In Vitro and In Vivo Activity against the Main Causative Agents of Cutaneous Leishmaniasis

The current standard of care for cutaneous leishmaniasis (CL) is organic antimonial compounds, but the administration of these compounds is complicated by a low therapeutic - toxic index, as well as parenteral administration. Thus, there is an urgent need for the development of new and inexpensive therapies for the treatment of CL. In this study, we evaluate the activity of the triphenylmethane (TPM) class of compounds against three species of Leishmania which are pathogenic in humans. The TPM have a history of safe use in humans, dating back to the use of the original member of this class, gentian violet (GV), from the early 20^th century. Initially, the in vitro efficacy against Leishmania (Viannia) braziliensis, L. (Leishmania) amazonensis and L. (L.) major of 9 newly synthesized TPM, in addition to GV, was tested. Inhibitory concentrations (IC) IC₅₀ of 0.025 to 0.84 µM had been found in promastigotes in vitro assays. The four most effective compounds were then tested in amastigote intracellular assays, resulting in IC₅₀ of 0.10 to 1.59 µM. A high degree of selectivity of antiparasitic activity over toxicity to mammalian cells was observed. Afterwards, GV and TPM 6 were tested in a topical formulation in mice infected with L. (L.) amazonensis leading to elimination of parasite burdens at the site of lesion/infection. These results demonstrated that TPM present significant anti-leishmanial activities and provide a rationale for human clinical trials of GV and other TPM. TPM are inexpensive and safe, thus using them for treatment of CL may have a major impact on public health.     

Synthesis,antitumor activity evaluation and mechanistic study of novel hederacolchiside A1 derivatives bearing an aryl triazole moiety

In an attempt to arrive at a more potent antitumor agent than the parent natural saponin hederacolchiside A₁, 23 hederacolchiside A₁ derivatives (4a-4w) were synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and screened in vitro for cytotoxicity against six human cancer cell lines. The structure-activity relationship of these compounds was elucidated, and the biological screening results showed that most of the compounds exhibited moderate to high levels of antitumor activities against the tested cell lines and some of them displayed more potent inhibitory activities compared with hederacolchiside A₁. Compound 4f showed a 2- to 7-fold more potent activity than hederacolchiside A₁. The mechanistic study of 4f revealed that this compound can induce cell apoptosis in HepG2 cells via mitochondrial-mediated intrinsic pathways.     

2-Benzoylbenzofuran derivatives possessing piperazine linker as anticancer agents

A series of novel 2-benzoylbenzofuran derivatives possessing piperazine linker have been prepared, and their in vitro anticancer activity against a panel of human tumor cell lines by MTT assay were evaluated. The results demonstrated that tertiary amine derivatives exhibited better cytotoxic activity, and SAR study revealed that electron-donating substituents on the phenyl ring of the derivatization functionality contributed to potent anticancer activities. Among them, compounds 6, 9, 11, 18, 23 and 25 displayed both better anti-tumor activity and lower cytotoxic effect on human normal liver cell L02. Further apoptosis analysis showed that compound 18 significantly induced apoptosis in A549 cell, which was considered as the most potent anticancer agent.     

Stereoselective synthesis of enantiopure N-substituted pyrrolidin-2,5-dione derivatives by 1,3-dipolar cycloaddition and assessment of their in vitro antioxidant and antibacterial activities

1,3-Dipolar cycloaddition between a chiral nitrone and N-substituted maleimides afforded unprecedented enantiopure spiro-fused heterocycles in good yields with a high enantio- and diastereoselectivity. The reaction was taking place on the less hindered face of the nitrone. The obtaining heterocycles were screened for their in vitro antioxidant properties and the results revealed that the potent antioxidant activity was generally recorded to compounds (3g) and (3e). The in vitro antibacterial activities of these two compounds were also investigated and the results demonstrated the strongest potential of compound (3g) against all the tested bacteria. Molecular properties were analyzed and showed good oral drug candidate like properties and that could be exploited as a potential antioxidant and antimicrobial agent. Finally, the preliminary results obtained from this investigation attempted to clarify if the structurally different side chains of active compounds interfere with their biological properties.     

Design,synthesis, and biological evaluation of 4-chloro-2H-thiochromenes featuring nitrogen-containing side chains as potent antifungal agents

A series of 4-chloro-2H-thiochromenes featuring nitrogen-containing side chains were designed, synthesized and tested in vitro for their antifungal activities. The results of preliminary antifungal tests showed that most target compounds exhibited good inhibitory activities against Candida albicans, Cryptococcus neoformans, Candida tropicalis. Notably, compounds 10e and 10y showed most potent activity in vitro against a variety of fungal pathogens with low MICs. Meanwhile, low cytotoxicity on mammalian cells has been observed for compounds 10e and 10y in the tested concentrations by the MTT assay. Therefore, the 4-chloro-2H-thiochromenes with nitrogen-containing groups provide new lead structures in the search for novel antifungal agents.     

Antiplasmodial and cytotoxic activity of lanostane type triterpenoids isolated from Leplaea mayombensis

Leplaeric acid E 5, leplazarin 6a and 21-epileplazarin 6b, three new 3,4-seco-lanostane type triterpenes have been isolated from the stem bark of Leplaea mayombensis (Pellegr.) Staner along with fourteen known compounds from the fruits and roots. Leplaeric acid E, leplazarin and 21-epileplazarin, 15-α-hydroxy-3,4-seco-lanosta-4(28),8,24-triene-3,21-dioic acid, mayomlactones A and B, lanosta-7,24-dien-3-one, leplaeric acid A, B and C were screened in vitro for antiplasmodial activity against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains of Plasmodium falciparum and for cytotoxicity against CAL-27, CaCo2, Skov-3, and HepG2 cells line. Three compounds including 15-α-hydroxy-3,4-seco-lanosta-4(28),8,24-triene-3,21-dioic acid (IC₅₀ 5.65–7.09 μM), lanosta-7,24-dien-3-one (IC₅₀ 7.18–9.07 μM), and leplaeric acid C (IC₅₀ 7.59–8.47 μM) were the most active against both strains of P. falciparum. All the compounds exhibited cytotoxicity against the three-cell lines with IC₅₀ ranging from 12.30 to 181.88 μM. These results confirm the usage of the medicinal plant L. mayombensis for the management of malaria and suggest that further lead optimization studies on potent compounds identified from this study could lead to the identification of potential of lead molecules as scaffold for new antimalarial drug discovery.     

Sulfur-containing natural hinduchelins derivatives as potential antifungal agents against Rhizoctonia solani

Aryl-oxazole alkaloids are an important class of heterocyclic natural products, and which has been demonstrated to exhibit broad biological functions. During the course of our research for highly active compounds from natural products, the natural hinduchelins A-D with typical aryl-oxazole unit have been synthesized and investigated. So, in order to develop highly potential functional molecules, a series of novel sulfur-containing aryl-oxazole compounds derived from natural hinduchelins was designed and synthesized, and their in vitro fungicidal activities against four common plant pathogenic fungi (oomycetes Phytophthora capsici, ascomycetes Sclerotinia sclerotiorum, deuteromycetes Botrytis cinerea and basidiomycetes Rhizoctonia solani) were evaluated, the results demonstrated that compounds 7b and 7c displayed good selectivity and specificity in vitro against basidiomycetes R. solani. In addition, the in vivo antifungal activities also indicated compounds 7b and 7c can protect the horsebean against infection by R. solani, and the possible mechanism of antifungal action for these compounds has also been investigated.