Medicinal Chemistry for Sustainable Development.

Pharmaceutical chemistry has many industrial processes that must be studied and adapted to a new reality where the environment must be the focus of all production chains. Thus, new technologies that are cleaner and use renewable sources of raw materials still need to be developed and applied to materials that go to the market, and they need to reach a level that is less harmful to the environment. This applies especially in areas related to the pharmaceutical industries since chemical products are used in the production of medicines and used in many other areas of everyday life and are included in the Sustainable Development Goals proposed by the United Nations. This article intends to provide insight into some relevant topics that can stimulate researchers toward medicinal chemistry that can contribute to a sustainable future of the biosphere. This article is structured around four interconnected themes that influence how green chemistry can be important for a future where science, technology and innovation are key to mitigating climate change and increasing global sustainability.

30th Annual GP2A Medicinal Chemistry Conference.

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP2A) held their 30th annual conference in August 2022 in Trinity College Dublin, Ireland. There were 9 keynote presentations, 10 early career researcher presentations and 41 poster presentations.

Platform headspace gas chromatography method for high-throughput determination of residual solvents in pharmaceutical materials.

Static headspace capillary gas chromatography (HSGC) has been employed to monitor the level of residual solvents in the pharmaceutical materials. Most of the HSGC methods, however, consume significant amounts of diluents and require considerable amount of sample preparation time. Accordingly, a HSGC method featured with fast turnaround time, and minimal amount of solvent use has been developed for the quantitative analysis of 27 residual solvents frequently used in the development and manufacturing processes of pharmaceutical industry. This HSGC-FID method employs a commercially available fused silica capillary column, a split injection (40:1), and a programmed temperature ramp. It was qualified for specificity, accuracy, repeatability/precision, linearity, LOQ, solution stability, and robustness using two representative sample matrices. The standards, samples and spiked samples were demonstrated to be stable for at least 10 days at room temperature in sealed headspace vials with a recovery of ≥ 93%. The method was also shown to be robust, and its performance was not affected by small changes of carrier gas flow rate, initial oven temperature or the headspace oven temperature. In this new approach, the analytical sample was prepared by dissolving the sample into 1 mL of the diluent and the standard solution was prepared by diluting 1 mL of the custom-made stock into 9 mL of the diluent whereas the traditional approach requires liters of the diluent, making the new approach environmentally friendly, sustainable, economical, agile, error-proofing and thus appropriate for a variety of pharmaceutical applications.

Modern Pharmacological Effect of Zhishi Xiebai Guizhitang： A Review / 中国实验方剂学杂志

Zhishi Xiebai Guizhitang is a classical prescription for the treatment of chest impediment with the method of warming Yang. It is included in the Catalogue of Ancient Classical Prescriptions issued by the National Administration of Traditional Chinese Medicine （First Batch）， with the effect of activating Yang， dissipating mass， moving Qi and resolving phlegm. Its main symptoms include chest fullness and pain， or even chest pain radiating to the back， wheezing， coughing， shortness of breath， and Qi reversal from the hypochondrium. In modern traditional Chinese medicine， Zhishi Xiebai Guizhitang is clinically used in the treatment of cardiovascular system， digestive system， respiratory system and other diseases， among which coronary heart disease， unstable angina pectoris， myocardial infarction， sinus bradycardia and other cardiovascular diseases have particularly significant effects. This paper reviewed the pharmacological studies of Zhishi Xiebai Guizhitang in the past 10 years. The results showed that each single medicine and the whole prescription alleviated the above cardiovascular diseases to a certain extent， with the pharmacological effects of improving intravascular environment， myocardial ischemia， myocardial ischemia-reperfusion injury， and myocardial hypoxia， anti-inflammation， plaque stabilisation， etc.， and the pharmacological mechanism involved the regulation of relevant active substances in vivo as well as related signaling pathways and ion channels， mainly including thromboxane B2 （TXB2）， prostacyclin I2（PGI2） and phosphatidylinositol 3-kinases/protein kinase B/endothelial nitric oxide synthase （PI3K/Akt/eNOS） signaling pathways， and ATP-sensitive potassium channels. In addition， the relationship between the pharmacological effects of some single medicines and transient receptor potential ankyrin 1 （TRPA1） has been reported that TRPA1 is a key to understanding the mechanism of Zhishi Xiebai Guizhitang in treating cardiovascular diseases， which is worth of further study.

Synthesis of a theranostic platform based on fibrous silica nanoparticles for the enhanced treatment of triple-negative breast cancer promoted by a combination of chemotherapeutic agents.

A new series of theranostic silica materials based on fibrous silica particles acting as nanocarriers of two different cytotoxic agents, namely, chlorambucil and an organotin metallodrug have been prepared and structurally characterized. Besides the combined therapeutic activity, these platforms have been decorated with a targeting molecule (folic acid, to selectively target triple negative breast cancer) and a molecular imaging agent (Alexa Fluor 647, to enable their tracking both in vitro and in vivo). The in vitro behaviour of the multifunctional silica systems showed a synergistic activity of the two chemotherapeutic agents in the form of an enhanced cytotoxicity against MDA-MB-231 cells (triple negative breast cancer) as well as by a higher cell migration inhibition. Subsequently, the in vivo applicability of the siliceous nanotheranostics was successfully assessed by observing with in vivo optical imaging techniques a selective tumour accumulation (targeting ability), a marked inhibition of tumour growth paired to a marked antiangiogenic ability after 13 days of systemic administration, thus, confirming the enhanced theranostic activity. The systemic nanotoxicity was also evaluated by analyzing specific biochemical markers. The results showed a positive effect in form of reduced cytotoxicity when both chemotherapeutics are administered in combination thanks to the fibrous silica nanoparticles. Overall, our results confirm the promising applicability of these novel silica-based nanoplatforms as advanced drug-delivery systems for the synergistic theranosis of triple negative breast cancer.

29th Annual GP2A Medicinal Chemistry Conference.

The 29th Annual GP2A (Group for the Promotion of Pharmaceutical chemistry in Academia) Conference was a virtual event this year due to the COVID-19 pandemic and spanned three days from Wednesday 25 to Friday 27 August 2021. The meeting brought together an international delegation of researchers with interests in medicinal chemistry and interfacing disciplines. Abstracts of keynote lectures given by the 10 invited speakers, along with those of the 8 young researcher talks and the 50 flash presentation posters, are included in this report. Like previous editions, the conference was a real success, with high-level scientific discussions on cutting-edge advances in the fields of pharmaceutical chemistry.

Development and implementation of an enterprise-wide predictive model for early absorption, distribution, metabolism and excretion properties.

Background: Accurate prediction of absorption, distribution, metabolism and excretion (ADME) properties can facilitate the identification of promising drug candidates. Methodology & Results: The authors present the Janssen generic Target Product Profile (gTPP) model, which predicts 18 early ADME properties, employs a graph convolutional neural network algorithm and was trained on between 1000-10,000 internal data points per predicted parameter. gTPP demonstrated stronger predictive power than pretrained commercial ADME models and automatic model builders. Through a novel logging method, the authors report gTPP usage for more than 200 Janssen drug discovery scientists. Conclusion: The investigators successfully enabled the rapid and systematic implementation of predictive ML tools across a drug discovery pipeline in all therapeutic areas. This experience provides useful guidance for other large-scale AI/ML deployment efforts.

Magnetic polymeric core-shell as a carrier for gradual release in-vitro test drug delivery.

At first functionalized graphene oxide was selected as a basic substrate obtained through process of functionalization of graphene oxide with diethylenetriamine as substrates. Then magnetic nanoparticle sediments were formed and coated on the functionalized graphene oxide as the core center. The core nanoparticle was added to a gel containing poly (lactic-co-glycolic acid), polyethylene glycol, and polyvinylpyrrolidone and nilotinib drug for forming a shell on the core. After separation and freeze-drying, single core-shell particles were obtained. The second shell was coated by dispersing first core-shell in a new gel containing polylactic acid, polyvinyl alcohol, polyethylene glycol, and nilotinib. The third layer was laminated on core-dual shell particle by entering in sodium alginate, polyethylene glycol, poly (lactic-co-glycolic acid), polylactic acid and nilotinib gel according to the same method used above. In order to determine the gradual release, the core-single, dual and triple shell nanoparticles dispersed in phosphate buffer saline at the several pHs (3, 5.4, 7.4) and as well as monitoring the released concentration of nilotinib by UV-Vis spectrophotometer technique. Core-triple shell particle had gradual release at three different rates over the long time. Finally, the average release rate for 400 mg of drug, in single layer, double-layer and three layers were reported to be equal to 15.8, 10.4 and 6.6 mg/h at intervals of 24, 37 and 60 h, respectively. The release rate of the drug reduced by increasing the pH value. All products were characterized using several techniques.

Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids.

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann's discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer's and Parkinson's disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward "green" syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

Highly productive and scalable approach to synthesize ticlopidine: A potent thienopyridine anti-platelet aggregation drug.

Ticlopidine (trade name Ticlid), an acidic thienopyridine derivative, is an effective, well-known and long-acting inhibitor of platelet aggregation. Because of its potent inhibitory activity for treating a variety of diseases, the development of efficient approaches for accessing ticlopidine represents an important endeavour. Therefore, in this research work, we developed a promising novel five-step synthetic approach for synthesizing ticlopidine. This method provides ticlopidine in 60% overall yield from readily available starting material viz. thiophene. In this methodology, all steps afforded excellent yields and are operationally simple and environmentally acceptable. This approach also offers various attractive advantages, for example, it's applicable for large-scale synthesis, has simple work-up procedures and short reaction times, and uses inexpensive and readily available reagents. Furthermore, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine is a key precursor for the synthesis of numerous bioactive compounds such as prasugrel and clopidogrel. This protocol provides 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in 62% overall yield via a 4-step synthetic approach.

Phytocannabinoids Profile in Medicinal Cannabis Oils: The Impact of Plant Varieties and Preparation Methods.

Cannabis (Cannabis sativa L.) is a highly promising medicinal plant with well-documented effectiveness and growing use in the treatment of various medical conditions. Cannabis oils are mostly used in galenic preparations, due to their easy adjustment of the administration dose, together with the enhanced bioavailability of its active compounds. As stated by the Italian Law (9/11/2015, 279 Official Gazette), "to ensure the quality of the oil-based cannabis preparation, the titration of the active substance(s) should be carried out." This study aims to represent the Italian panorama of cannabis oils, which were analyzed (8,201) to determine their cannabinoids content from 2017 to 2019. After application of the exclusion criteria, 4,774 standardized cannabis oils were included, which belong to different medicinal cannabis varieties and prepared according to different extraction methods. The concentration of the principal cannabinoids was taken into account dividing samples on the basis of the main extraction procedures and cannabis varieties. According to this analysis, the most substantial variations should be attributed to different cannabis varieties rather than to their extraction protocols. This study may be the starting point of preparatory pharmacists to assess the correct implementation of the preparation procedures and the quality of the extracts.

Induced mathematical filtration as an innovative strategy for discrimination and estimation of glycemic control drugs in fixed dose combination.

An innovative strategy was developed for the estimation of a fixed dose combination containing Alogliptin (ALO) and pioglitazone (PIO) using induced concept for resolving the overlapped spectra, lacking isoabsorptive point. This strategy is based on coupling factors as numerical values or ratios as spectrum form with the recorded signals leading to induced mathematical filtration of the drug of interest and complete elimination of the interfering one in the combination without prior physical separation. The calculated factors were factor of equality in induced dual wavelength (IDW) or absorptivity factor in induced concentration subtraction method (ICS) while absorptivity ratio spectrum for induced amplitude modulation method (IAM). The calibration curves displayed linearity within 1.0-16.0 µg/mL for ALO and 2.0-22.0 µg/mL for PIO with good correlation coefficients. The induced methods specificity was also assured through the assaying different synthetic mixtures prepared to contain the two drugs in ratios approaching the ratio actually found in the marketed dosage form. The methods were applicable and suitable for estimating ALO and PIO in both bulk form and their fixed dose combination. Induced methods have been extensively validated in accordance with ICH guidelines and results demonstrated the accuracy and reproducibility in comparison to the reported method.

Synthesis and biological properties of a series of aryl alkyl disulfide derivatives.

Disulfide containing compounds are recognized for their wide range of biological properties and are known for their important applications in the pharmaceutical field. In this study, a series of diaryl disulfides with varying alkyl chain length (C8-C16) was synthesized and assessed for their physicochemical and biological properties. The interactions of compounds with bovine serum albumin (BSA) was investigated in order to study their ability to bind with blood serum protein. An increase in the binding constants (Ka) was observed with increasing chain length C8-C12, while a decrease in value was obtained with compounds of chain length C14 and C16 showing a cut off effect at C12. The thermodynamic parameters of binding indicated that the compounds bound to BSA mostly by van der Waals forces and hydrogen bonding. Molecular docking studies showed that the diaryl disulfides displayed greater binding affinity to Trp 213 rather than the Trp 134 residue on the BSA molecule. The trend observed in molecular docking is in line with the fluorescence binding studies whereby the C12 derivative was found to show optimum affinity with BSA. The disulfide with chain length C10 showed moderate antibacterial activity the highest inhibitory activity against Bacillus cereus. The cytotoxicity of the disulfides towards HaCaT cells decreased from C8 to C14. The overall results obtained show that these disulfides have potent antibacterial properties against Gram-positive bacteria Bacillus cereus at concentrations which are relatively non-toxic to normal cells.

Reductive metabolites of curcumin and their therapeutic effects.

Curcumin, a secondary metabolite from the turmeric plant is one of the most promising natural products, which has been studied extensively for decades. It has demonstrated several pharmacological activities in vitro and in vivo. Various studies have indicated that the pharmacological activity of curcumin is contributed by its metabolites. The aim of this review is to present an overview of metabolic products of curcumin produced upon its reduction like di, tetra, hexa and octa-hydrocurcumin. In addition, this paper has systematically analyzed the current information regarding medicinal use of reduced metabolites of curcumin and identified the limitations which have hindered its widespread usage in the medical world. Several diverse therapeutic effects have shown to be exhibited by reduced metabolites of curcumin such as antioxidant, anti-cancerous, anti-inflammatory and immunoregulatory activities. The potential underlying molecular mechanisms of the biological activities of reduced metabolites of curcumin have also been highlighted, which may provide insight into the principle of effectiveness of curcumin.

Experimental approach, theoretical investigation and molecular docking of 2- chloro-5-fluoro phenol antibacterial compound.

The molecular structural dimerization of biologically potent 2-chloro-5-fluoro phenol (2C5FP) is optimized. A combined experimental and theoretical characteristics of vibrational spectral determinations (NMR, FT-IR and Raman) on 2-chloro-5-fluoro phenol (2C5FP) were used at DFT-B3LYP/6-31++G (d,p) level of computation. A close coherence is achieved when experimentally observed wave numbers are compared with calculated wave numbers by refinement of the scale factors. Calculated values of global chemical descriptors of the present molecule reveal significant molecular stability and chemical reactivity. Non-Linear optical (NLO) property of the present molecule is investigated by determining the second order non linear parameter of first hyperpolarizability ß. Moreover, hydrogen bond and thermodynamic parameters at various temperatures are determined and discussed. Investigated compound 2C5FP possesses a better antibacterial activity against Echerichia coli, Streptococcus aureus, Pseudomonas aureus,and Staphylococcus aureus, respectively. The title molecule is subjected to molecular docking studies with two different proteins, namely Staphylococcus aureus Tyrosyl-tRNA synthetase (PDB ID: 1JIL) and human dihydroorotate dehydrogenase (hDHODH) (PDB ID: 6CJF). The results of molecular docking analysis support the antibacterial activity and demonstrate a strong interaction with the DHODH inhibitor.

Structure-based drug designing of naphthalene based SARS-CoV PLpro inhibitors for the treatment of COVID-19.

The emergence of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has imposed a greater challenge for the world. Coronavirus has infected over 38.3 million people and caused millions of deaths worldwide. The COVID-19 outbreak has accentuated the need for additional efforts to develop broad-spectrum therapeutics to combat SARS-CoV-2 infection. In the current investigation, an attempt was made to design potential SARS-CoV PLpro inhibitors containing naphthalene and 3,4-dihydro-2H-pyran moieties connected via -NHCO- linker. The ligands obeyed Lipinski's rule and were found to have good drug-likeness and ADMET properties. Docking simulations confirmed strong binding affinity and inhibition potential of the designed ligands against the receptor SARS CoV-2 Papain-like protease (PLpro). LigandL10 incorporating the oxadiazole ring system displayed better binding affinity than the control 5-acetamido-2-methyl-N-[(1R)-1-naphthalen-1-ylethyl]benzamide. Further, the docked complex of LigandL10 was subjected to molecular dynamics (MD) simulation to examine the molecular mechanisms of protein-ligand interactions. The results of the present study are encouraging. Ligand L10 emerged as the most potent ligand in the series and could be considered for further research for the development of potential therapeutics for the treatment of COVID-19.

Iodine-131 labeled genistein as a potential radiotracer for breast cancer.

OBJECTIVE: Genistein is an isoflavone compound that has been proven to have anticancer activity and is capable of binding to estrogen ß receptors with Selective Estrogen Receptor Modulators (SERMs) properties, and has a strong affinity to inhibit the development of cancer cells. This study is to determine the optimum conditions of the reaction in the synthesis process of compounds labeled 131I-genestein which can be potential for application of breast cancer diagnosis. METHODS: Synthesis of 131I-Genistein compound labeling using the Chloramine-T iodination method. This method uses several parameter optimizations, including: pH conditions, the amount of chloramine-T oxidizer and sodium metabisulfite reducing agent. The radiochemical purity of the 131I-Genistein compound was determined using thin layer chromatography TLC-SG F254, and measured by SCA (Single Channel Analyzer). The radiochemical purity of labeled compounds must fulfill the requirements of the United States of Pharmacopeia. RESULTS: Optimization of the synthesis conditions of the 131I-Genistein compound was obtained at pH 8, the amount of chloramine-T 0.225 mg, and the amount of Na-Metabisulfite 0.342 mg, with 30 min reaction time. This optimum condition produces radiochemical purity of 95.02 ± 0.76%. CONCLUSION: Products labeled 131I-Genistein meet radiochemical purity requirements according to USP requirements. The labeled compound is expected to be able to be used to detect breast cancer through a binding mechanism with estrogen receptors ß.

Synthesis, molecular docking, antiplasmodial and antioxidant activities of new sulfonamido-pepetide derivatives.

Twenty-three new series of toluene-sulfonamide dipeptide derivatives were synthesized and screened for antiplasmodial and antioxidant potencies. Many of the derivatives were active against Plasmodium falciparum with IC50 ranging from 3.20 - 9.10 µM. The ability of compounds 7h, 7m and 7n (IC50 of 7.53, 7.21 and 6.01 µg/mL respectively) to scavenge DPPH free radicals were comparable to that of ascorbic acid. Additionally, molecular docking disclosed that four compounds exhibited theoretical inhibition constant at submicromolar concentrations (K i = 0.72, 0.75, 0.57, and 0.53 µM respectively) compare to the reference ligand (a pyrazole sulfonamide; K i = 0.01 µM). Overall, some of the derivatives possess antimalarial property as well as the ability to inhibit oxidative stress in malaria pathophysiology; and hence, are good candidates for further antimalarial drug research.

Anti-tumor effects of Artemisia nilagirica extract on MDA-MB-231 breast cancer cells: deciphering the biochemical and biomechanical properties via TGF-ß upregulation.

PURPOSE: Artemisia nilagirica (AN), which is known to have antimicrobial, antioxidant, antiulcer, and anti-asthmatic properties, has been recently shown to have anti-cancer activity. However, the mechanism responsible for the anti-cancer property and its effect on cellular properties and functions are not known. MATERIAL AND METHODS: We have characterized the biochemical and biomechanical properties of MDA-MB-231 cells treated with the methanolic extract from AN. RESULTS: We show that AN-treatment decreases cell-eccentricity, increases expression of actin and microtubules, and do not affect cell-area. Increased expression of cytoskeletal proteins is known to change the mechanical properties of the cells, which was confirmed using micropipette aspiration and Atomic Force Microscopy. We identified the upregulation of the tumorigenic pathway (TGF-ß) leading to activation of Rho-A as the molecular mechanism responsible for actin upregulation. Since the initial stages of TGF-ß upregulation are known to suppress tumor growth by activating apoptosis, we hypothesized that the mechanism of cell death due to AN-treatment is through TGF-ß activation. We have validated this hypothesis by partially recuing cell death through inhibition of TGF-ß using Alk-5. CONCLUSION: In summary, our study reveals the mechanism of action of Artemisia nilagirica using a synergy between biochemical and biomechanical techniques.