Sterigmatocystin Limits Plasmodium falciparum Proliferation and Transmission

As part of our drug discovery program against malaria, the Penicillium janthinellum extract was discovered to inhibit P. falciparum proliferation in blood and transmission to mosquitoes. Bioactivity-guided fractionation of P. janthinellum extraction was carried out using chromatographic techniques. We determined the activities of fractions against Plasmodium falciparum asexual stage parasite proliferation in culture and sexual stage parasite transmission to mosquitoes using standard membrane feeding assays (SMFA). One active compound was isolated. Based on mass spectrometry and nuclear magnetic resonance profiles, the compound was structurally determined to be sterigmatocystin. Sterigmatocystin inhibited P. falciparum proliferation in the blood with an IC50 of 34 µM and limited the sexual parasites to infect mosquitoes with an IC50 of 48 µM. Meanwhile, sterigmatocystin did not show any acute toxicity to human kidney cells at a concentration of 64 µM or lower. Sterigmatocystin can be used as a drug lead for malaria control and as a probe to understand molecular mechanisms of malaria transmission.

Chalcone Scaffolds, Bioprecursors of Flavonoids: Chemistry, Bioactivities, and Pharmacokinetics

Chalcones are secondary metabolites belonging to the flavonoid (C6-C3-C6 system) family that are ubiquitous in edible and medicinal plants, and they are bioprecursors of plant flavonoids. Chalcones and their natural derivatives are important intermediates of the flavonoid biosynthetic pathway. Plants containing chalcones have been used in traditional medicines since antiquity. Chalcones are basically α,β-unsaturated ketones that exert great diversity in pharmacological activities such as antioxidant, anticancer, antimicrobial, antiviral, antitubercular, antiplasmodial, antileishmanial, immunosuppressive, anti-inflammatory, and so on. This review provides an insight into the chemistry, biosynthesis, and occurrence of chalcones from natural sources, particularly dietary and medicinal plants. Furthermore, the pharmacological, pharmacokinetics, and toxicological aspects of naturally occurring chalcone derivatives are also discussed herein. In view of having tremendous pharmacological potential, chalcone scaffolds/chalcone derivatives and bioflavonoids after subtle chemical modification could serve as a reliable platform for natural products-based drug discovery toward promising drug lead molecules/drug candidates.

Chalcones identify cTXNPx as a potential antileishmanial drug target

With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2’,6’-dihydroxy-4’-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2’,4’,6’- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones.

A Review on Diversity of Anticancer Compounds Derived from Indonesian Marine Sponges

As a tropical archipelago country, Indonesia has a mega diversity of marine organisms, such as sponges. About 850 species of sponges were identified from the east part of Indonesia. The uniqueness of Indonesian marine sponges attracted many researchers to explore the sponge’s potential in producing active substances. During 1995-2016, about 40 genera of Indonesian sponges were investigated for their potential in producing pharmacological activity such as antimicrobial, anticancer, antivirus, multidrug-resistant (MDR), etc. The data showed that 56.7% of 430 reported compounds were confirmed as new compounds. The research trend on Indonesian sponges was high during 2004-2013, but decreasing after 2014. However, researches in the term of active substances from marine sponges should find provide the basic skeleton of anti-cancer drug lead compounds. Chemical structure diversity plays an important role in the exploration of anticancer lead compounds. The purpose of this paper is to review the potential of anticancer diversity compounds derived from Indonesian sponges, to get comprehensive data for further investigation. As the conclusion of our review, the most anticancer compounds derived from Indonesian marine invertebrates are alkaloid groups (such as aaptamine, manzamine, and bromopyrrole derivatives), then terpenoid groups (such as diterpene, coelodiol, and coeloic acid, sesquiterpene aminoquinone, and also (+)-curcuphenol and (+)-curcudiol), and also from the other groups such as sterole, peptide, polyketide, amino acid derivatives, natural organic acid, and quinone. The most effective anticancer compounds were 5-benzoyldemethylaaptamine, isoaaptamine, 3-bromofascaplysin, hyrtioreticulins A, stylissamide X, sigmosceptrellin B, and diacarperoxide S.

Pharmacological Properties of 2,4,6-Trihydroxy-3-Geranyl Acetophenone and the Underlying Signaling Pathways: Progress and Prospects

2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a bioactive phloroglucinol compound found in Melicope pteleifolia (Champ. ex Benth.) T.G.Hartley, a medicinal plant vernacularly known as “tenggek burung”. A variety of phytochemicals have been isolated from different parts of the plant including leaves, stems, and roots by using several extraction methods. Specifically, tHGA, a drug-like compound containing phloroglucinol structural core with acyl and geranyl group, has been identified in the methanolic extract of the young leaves. Due to its high nutritional and medicinal values, tHGA has been extensively studied by using various experimental models. These studies have successfully discovered various interesting pharmacological activities of tHGA such as anti-inflammatory, endothelial and epithelial barrier protective, anti-asthmatic, anti-allergic, and anti-cancer. More in-depth investigations later found that these activities were attributable to the modulatory actions exerted by tHGA on specific molecular targets. Despite these findings, the association between the mechanisms and signaling pathways underlying each pharmacological activity remains largely unknown. Also, little is known about the medicinal potentials of tHGA as a drug lead in the current pharmaceutical industry. Therefore, this mini review aims to summarize and relate the pharmacological activities of tHGA in terms of their respective mechanisms of action and signaling pathways in order to present a perspective into the overall modulatory actions exerted by tHGA. Besides that, this mini review will also pinpoint the unexplored potentials of this compound and provide some valuable insights into the potential applications of tHGA which may serve as a guide for the development of modern medication in the future.

VIRTUAL SCREENING STATEGIES IN DRUG DISCOVERY – A BRIEF OVERVIEW

Computer-aided drug design has now become a compulsory tool in the drug discovery and development process which uses computational approaches to discover potential compounds with expected biological activities. Firstly, this review provides a comprehensive introduction of the virtual screening technique, knowledge and advances in both SBVS and LBVS strategies also presented. Secondly, recent database of compounds provided worldwide and drug-like parameters which are helpful in supporting the VS process will be discussed. These information will provides a good platform to estimate the advance of applying these techniques in the new drug-lead identification and optimization.

Drug-Lead Anti-tuberculosis Phytochemicals: A Systematic Review

Today, the occurrence and recurrence of multidrug-resistant tuberculosis (MDR-TB) strains and TB-comorbidity incidence are the main reasons for long-term morbidity and mortality from tuberculosis (TB) caused by the nasty acid-fast pathogen, Mycobacterium tuberculosis, globally. Therefore, discovering and developing well-tolerated and non-toxic anti-TB regimens are directly needed to defend the gruesome MDR-TB strains and support WHO’s ‘END-TB’ campaign. Alternatively, phytochemicals from various common and medicinal plants have always been vital therapeutic agents since the primitive era. Thus, to promote phytochemical-based anti-TB drug development, scientific documentation of biological activities, structural-cum-drug chemistry analyses are essential. In the present review, we have used some specific keywords such as ‘antituberculosis phytochemicals’, 'antituberculosis phytochemicals from plant source', ‘natural products against tuberculosis’ in Google, PubMed, ScienceDirect sites to get more appropriate research reports/ publications. Further, based on lower minimum inhibitory concentration (MIC) within 50 µg/mL, a total of two-hundred-twenty-one bioactive anti-TB phytochemicals were selected for critical drug-chemistry and structural activity relationship (SAR) analyses to accelerate the anti-TB drug development with most drug lead anti-TB candidates. Among all, abietane, ethyl-p-methoxycinnamate, ergosterol peroxide, mono-O-methyl curcumin isoxazole, 7-methyljuglone, 12-demethylmulticaulin, 12-methyl-5-dehy droacetylhorminone, tryptanthrin, etc. are some of the potential anti-TB phytochemicals display at the minimum concentration ≤ 1 µg/mL. Remarkably, existing and clinical drug pipelines for TB contain more than one phytochemical scaffold/ pharmacophores illustrated from the SAR analysis. Thus, updated experimental documentation and critical drug-chemistry analysis on isolated phytochemicals are more beneficial for drug developers, R & D centres and pharmaceutical companies to accelerate the anti-TB drug development.

From Genome to Drugs: New Approaches in Antimicrobial Discovery

Decades of successful use of antibiotics is currently challenged by the emergence of increasingly resistant bacterial strains. Novel drugs are urgently required but, in a scenario where private investment in the development of new antimicrobials is declining, efforts to combat drug-resistant infections become a worldwide public health problem. Reasons behind unsuccessful new antimicrobial development projects range from inadequate selection of the molecular targets to a lack of innovation. In this context, increasingly available omics data for multiple pathogens has created new drug discovery and development opportunities to fight infectious diseases. Identification of an appropriate molecular target is currently accepted as a critical step of the drug discovery process. Here, we review how diverse layers of multi-omics data in conjunction with structural/functional analysis and systems biology can be used to prioritize the best candidate proteins. Once the target is selected, virtual screening can be used as a robust methodology to explore molecular scaffolds that could act as inhibitors, guiding the development of new drug lead compounds. This review focuses on how the advent of omics and the development and application of bioinformatics strategies conduct a “big-data era” that improves target selection and lead compound identification in a cost-effective and shortened timeline.