Natural Indole Alkaloids from Marine Fungi: Chemical Diversity and Biological Activities

The indole scaffold is one of the most important heterocyclic ring systems for pharmaceutical development, and serves as an active moiety in several clinical drugs. Fungi derived from marine origin are more liable to produce novel indole-containing natural products due to their extreme living environments. The indole alkaloids from marine fungi have drawn considerable attention for their unique chemical structures and significant biological activities. This review attempts to provide a summary of the structural diversity of marine fungal indole alkaloids including prenylated indoles, diketopiperazine indoles, bisindoles or trisindoles, quinazoline-containing indoles, indole-diterpenoids, and other indoles, as well as their known biological activities, mainly focusing on cytotoxic, kinase inhibitory, antiinflammatory, antimicrobial, anti-insecticidal, and brine shrimp lethal effects. A total of 306 indole alkaloids from marine fungi have been summarized, covering the references published from 1995 to early 2021, expecting to be beneficial for drug discovery in the future.

Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors

A total of 20 novel aryl piperazine derivatives were designed and synthesized, and their structures were confirmed by mass spectrometry and nuclear magnetic resonance analyses. Their 5-HT1A and sigma-1 receptor affinities were determined, and six of them showed high affinities (K i < 20 nmol/L) to both 5-HT1A and sigma-1 targets. Then, metabolic stability (T 1/2) tests of six compounds in rat and human liver microsomes were performed. Our data indicated that compound 27 has both high affinity for 5-HT1A and sigma-1 receptors (5-HT1A: K i = 0.44 nmol/L; sigma-1: K i = 0.27 nmol/L), and good metabolic stability (T 1/2 values are 21.7 and 24.6 minutes, respectively). Interestingly, results from the forced swimming test, mouse tail suspension test, and preliminary pharmacokinetic test suggested the marked antidepressant activity, good pharmacokinetic characteristics, and low toxicity of compound 27 in the two models. In conclusion, compound 27 has great value of further study as an active molecule of antidepressant drugs.

Enhancement of Aqueous Solubility, Dissolution Profile, and Oral Bioavailability of Pentoxifylline by Microsponges

Microsponge, a novel drug delivery system, is designed to deliver a pharmaceutically active ingredient efficiently at the minimum dose. Microsponge plays an important role in enhancing drug stability, reducing side effects, and modifying drug release profiles. It is mostly used for transdermal delivery. Recent studies also explored their use for oral administration. This study aimed to explore the potential use of the microsponge technique in improving the aqueous solubility and dissolution profile of pentoxifylline (PTX). In this study, microsponges were prepared by a quasi-emulsion solvent diffusion method by varying concentrations of carriers. Nine different ratios of the PTX:Eudragit E-100 with varying amounts of dichloromethane were used. All formulated microsponges were evaluated for %production yield, compatibility of drug excipient, encapsulation efficiency, in vitro drug release, and in vivo bioavailability, as well as recorded by scanning electron microscopy (SEM) and differential scanning calorimetry(DSC). Our data suggested that the aqueous solubility of PTX microsponges was four times greater than that of pure drug. The in vitro drug release of selected microsponges (M8) was found to be 70%; furthermore, the in vivo study suggested that the selected formulation significantly enhanced drug concentration in the plasma (9,219 ng/mL in 12 hours) in comparison to pure drug PTX (2,476 ng/mL in 12 hours). SEM showed that the prepared microsponges were spherical with porous nature. Fourier-transform infrared spectroscopy and DSC studies confirmed an absence of incompatibility among drugs and selected excipients. The pH of the selected gel was found to be 6.8, which was compatible with those of skin and oral formulations also. All above data suggested a highly successful and beneficial use of the microsponge technique in enhancing aqueous solubility, dissolution profile, and oral bioavailability of PTX. Microsponge-based delivery of PTX may represent an alternative strategy to improve the bioavailability of the drug.

Metal Complexes as DNA Synthesis and/or Repair Inhibitors: Anticancer and Antimicrobial Agents

Medicinal inorganic chemistry involving the utilization of metal-based compounds as therapeutics has become a field showing distinct promise. DNA and RNA are ideal drug targets for therapeutic intervention in the case of various diseases, such as cancer and microbial infection. Metals play a vital role in medicine, with at least 10 metals known to be essential for human life and a further 46 nonessential metals having been involved in drug therapies and diagnosis. These metal-based complexes interact with DNA in various ways, and are often delivered as prodrugs which undergo activation in vivo. Metal complexes cause DNA crosslinking, leading to the inhibition of DNA synthesis and repair. In this review, the various interactions of metal complexes with DNA nucleic acids, as well as the underlying mechanism of action, were highlighted. Furthermore, we also discussed various tools used to investigate the interaction between metal complexes and the DNA. The tools included in vitro techniques such as spectroscopy and electrophoresis, and in silico studies such as protein docking and density-functional theory that are highlighted for preclinical development.

Enantioselective aza-Michael Cyclization Reaction Catalyzed by Quinine-Derived Monoquaternary Ammonium Salts: an Effective Route to Synthesize Letermovir

A series of mono- or bis-quaternary ammonium salts derived from cinchonidine or quinine was synthesized and screened as potent phase-transfer catalysts for the reaction of aza-Michael cyclization, the key step in the synthesis of letermovir. During the reaction of aza-Michael cyclization, the screened monoquaternary ammonium salt quinine derivative Q1 transferred 7 to 8 with 91.9% yield and 58% ee. The application of Q1 was preferred, due to its enantioselectivity, the possibility of reuse, and the lower cost in large-scale preparation. Furthermore, the racemization condition of letermovir enantiomer was also explored for the possibility to develop the resolution/racemization process. With the optimal catalyst Q1 in hand, the synthesis of letermovir may be more convenient and economical in the future.

Size-Adjustable Nano-Drug Delivery Systems for Enhanced Tumor Retention and Penetration

Over the past decades, nano-drug delivery systems have shown great potential in improving tumor treatment. And the controllability and design flexibility of nanoparticles endow them a broad development space. The particle size is one of the most important factors affecting the potency of nano-drug delivery systems. Large-size (100–200 nm) nanoparticles are more conducive to long circulation and tumor retention, but have poor tumor penetration; small-size (<50 nm) nanoparticles can deeply penetrate tumor but are easily cleared. Most of the current fixed-size nanoparticles are difficult to balance the retention and penetration, while the proposal of size-adjustable nano-drug delivery systems offers a solution to this paradox. Many endogenous and exogenous stimuli, such as acidic pH, upregulated enzymes, temperature, light, catalysts, redox conditions, and reactive oxygen species, can trigger the in situ transformation of nanoparticles based on protonation, hydrolysis, click reaction, phase transition, photoisomerization, redox reaction, etc. In this review, we summarize the principles and applications of stimuli-responsive size-adjustable strategies, including size-enlargement strategies and size-shrinkage strategies. We also propose the challenges faced by size-adjustable nano-drug delivery systems, hoping to promote the development of this strategy.

Enhanced Efficacy and Reduced Hepatotoxicity by Combination of Gnaphalium affine Extract and Benzbromarone in the Treatment of Rats with Hyperuricemic Nephropathy

Simultaneous oral intake of herbal medicine with chemical drugs may result in beneficial pharmacodynamic efficacy, including additive and synergistic effects with reduced toxicity. Gnaphalium affine D. Don (GAD) is a traditional Chinese Medicine that has been used for the management of hyperuricemia and gout. Benzbromarone (BBR) is one of the first-line drugs used for urate-lowering therapy in China but is toxic to the liver. The present study aimed to determine the effects of GAD and BBR, both alone and in co-treatment (with dosing interval of 1 hour), on chronic hyperuricemic nephropathy (HN) and hepatotoxicity in rats. Our data indicated that GAD significantly inhibited the elevation of serum uric acid, blood urea nitrogen, and creatinine levels in chronic HN rats at doses of 450 and 900 mg/kg/day. The rise in serum alanine aminotransferase and aspartate aminotransferase in BBR (or vehicle)-treated HN rats was significantly reduced by pre- (or post)-administration of GAD (450 mg/kg/day). The q-value >1.15 (by Jin method) indicated synergistic effects of co-treatments of BBR (50 mg/kg) with GAD (450 mg/kg). The synergistic beneficial effects were validated by comparison of BBR alone at a dose of clinical usage (4.5 mg/kg/day, in two divided doses) and BBR + GAD at half dose plus half dose (2.25 + 225 mg/kg/day) or half dose plus full dose (2.25 + 450 mg/kg/day). In conclusion, co-treatment with GAD and BBR holds promise for the management of hyperuricemia and gout.

Progress in the Synthesis of Heterocyclic Compounds Catalyzed by Lipases

Heterocyclic compounds are representative of a larger class of organic compounds, and worthy of attention for many reasons, chief of which is the participation of heterocyclic scaffolds in the skeleton structure of many drugs. Lipases are enzymes with catalytic versatility, and play a key role in catalyzing the reaction of carbon–carbon bond formation, allowing the production of different compounds. This article reviewed the lipase-catalyzed aldol reaction, Knoevenagel reaction, Michael reaction, Mannich reaction, etc., in the synthesis of several classes of heterocyclic compounds with important physiological and pharmacological activities, and also prospected the research focus in lipase-catalyzed chemistry transformations in the future.

Finding Use for Sorghum Bicolor Leaf Sheath in Coating Technology

This study aimed to investigate the potential use of aqueous extract of Sorghum bicolor leaf sheath (SBLS) as a coating agent for paracetamol tablets. The mechanical properties of the coated tablets were assessed using crushing strength and friability test, while the release properties of the tablet were evaluated using disintegration and dissolution tests. The physicochemical properties of the coated tablets did not show any striking differences when compared with the uncoated tablet as par compendium specifications, which formed the basis for performing further in vitro dissolution study. Our data showed that SBLS enhanced the hardness and friability of the tablets in a dose-dependent manner. Tablets coated with 3, 5, and 7.5% of SBLS disintegrated in 8.13, 6.25, and 4.13 minutes, respectively, while the uncoated tablet disintegrated in 0.7 minutes. Furthermore, 3, 5, and 7.5% of SBLS-coated tablets exhibited slower release of their active ingredient (releasing 21, 16, and 17%, respectively) than that of the uncoated tablet (releasing 40%) in 5 minutes. Besides, comparison between the dissolution profiles was successfully achieved using difference factor (f1) and similarity factor (f2). The apparent dissimilarity between our coated tablets and the uncoated one led to further study of convolution in vitro–in vivo correlation, with the aim to obtain data that converted into mathematical prediction of in vivo data. For all batches, the percent predictable errors of C max and T max were within the acceptable limit of no more than 10%. In summary, SBLS aqueous extract is a potential and protective coat agent for paracetamol tablets. The in vitro established dissolution of the coated tablets provided scientific information for the prediction of the in vivo plasma drug profile.

Asymmetric Synthesis of 1,2-Limonene Epoxides by Jacobsen Epoxidation

This study reported an asymmetric synthesis of 1,2-limonene epoxides. The absolute stereochemistry was controlled by a Jacobsen epoxidation of cis-1,2-limonene epoxide (with diastereomeric excess of 98%) and trans-1,2-limonene epoxide (with diastereomeric excess of 94%), which could be used as important raw materials for the preparation of related cannabinoid drugs.