Letters in Drug Design & Discovery - Volume 21, Issue 1, 2024

Following the coronavirus outbreak, global efforts to find a vaccine and drug affecting Covid- 19 have been widespread. Reusing some of the available drugs has had relatively satisfactory results. One of the classes of drugs studied against SARS-CoV-2 is the HDAC inhibitors collected in this review. Among the most important points of this study can be mentioned: (a) SARS-COV-2 infection can influence the ACE/ACE2-ATR1-Cholesterol-HDAC axis signaling, (b) By limiting endocytosis and decreasing ACE2-spike protein recognition at the same time, Romidepsin may hinder SARS-2-S-driven host cell entry. (c) HDAC inhibitors affect the expression of ABO, ACE2 and TMPRSS2 in epithelial cell lines. (d) Valproic acid may help to reduce ARDS as well as hospitalizations and death. (e) Trichostatin A inhibits antigen expression, viral RNA load and infectious particle production in SARS-CoV-2.

Dihydropyridine is an outstanding heterocyclic compound with a wide range of pharmacological potential, including antimicrobial, antioxidant, antitubercular, antiarrhythmic, insecticidal, antihypertensive, vasodilator, anti-inflammatory, antibacterial, antidiabetic and superlative moiety in drug discovery. It is also a versatile pharmacophore, a privileged scaffold, and a distinguished heterocyclic compound. Excellent outcomes have already been shown with novel targets and various modes of action for the dihydropyridines hybrids. This review focused on the mode of action, synthesis, and biological activities. As a result, numerous dihydropyridine candidates are undergoing clinical studies to treat various disorders. This article highlights how novel techniques were used to create dihydropyridines, which may be helpful to researchers in the future.

Background: Natural products have been important resources for potential drug development. Among the many classes of natural products, alkaloids have the most therapeutic applications. Treatment of leishmaniasis by chemical drugs remains a challenge because of toxic side effects, limited efficacy, and drug resistance. This review focuses to embrace all researches on leishmanicidal alkaloids over a specific range of time, with special consideration the molecular mechanism of action, and structure-related activity.Methods: All publications (in English) from Web of Science, PubMed, Science Direct, Scopus, and Google Scholar from 2000-2021 using a variety of keywords such as natural alkaloids, herbal alkaloids, marine alkaloids along with leishmaniasis were included in the present study. In this summary, the focus is mainly on natural alkaloids of plant, mineral, marine origin, etc., which have empirically demonstrated the antileishmanial effect.Results: Fourteen categories of alkaloids with anti-leishmaniasis activity were extracted from the articles. The highest number of alkaloids belonged to isoquinoline, indole, and quinoline alkaloids (21.78%, 20.67%, and 16.48% respectively). This review indicated that the mentioned alkaloids are able to inhibit the proliferation of parasites, the respiratory chain and protein synthesis, arrest the cell cycle, disrupt the mitochondrial membrane integrity, inhibit leishmanial topoisomerase, induce mitochondrial dysfunction, and changes in the parasite morphology.Discussion: The present study highlighted antileishmanial alkaloids that are active against different species of Leishmania in vitro and some of them are also active in visceral and cutaneous leishmaniasis models. However, more clinical studies are needed to clarify the anti-leishmanial activity of alkaloids against leishmania in detail.Conclusion: Among the reported compounds, two main classes of alkaloids including isoquinoline and indole alkaloids cover a wider range of anti-parasitic compounds, and structure-activity relationships (SAR) studies of these molecular skeletons may be good lead compounds and afford the structural clues to develop novel medicines with more selective therapeutic profiles.

Neurological or brain disorders are increasingly recognized as major causes of death and disability worldwide, eventually leading to the burden of non-communicable and communicable diseases in the world. Biodegradable functions of polymers provide promising solutions to meet the therapeutic needs of neurological disorders owing to advantages such as the usage of biodegradable polymers in drug delivery approaches, which has become noticeable due to their biocompatibility and degradability properties. Due to such properties, they are degraded inside the body to produce natural/ nontoxic byproducts such as water and carbon dioxide and hence eliminated easily. Sustained drug delivery by biodegradable polymer devices can increase the therapeutic efficacy of drugs by producing high local tissue concentrations over extended periods of time. This review discusses recent progress in the research and development of biodegradable polymers, including their nanoformulation approaches.

Fused nitrogen-containing heterocyclic compounds have been identified to display a prominent role in medicinal chemistry, biochemistry, and other streams of science. Countless derivatives of pyrazolo[ 1,5-a] pyridine have been investigated by researchers for their distinct pharmacological characterization. In this article, we have revealed and arranged the various routes of synthesis and therapeutic activities such as dopamine binding affinity, kinase inhibitory activity, and PDE inhibitors of pyrazolo[1,5- a]pyridine-containing compounds which have been explored till now. The remarkable outcomes obtained via in vitro as well as in vivo profile screening of this moiety and its derivatives lead this scaffold to be recognized to a greater extent and examined further for better results. This review will give medicinal chemists a flying-bird eye catch view of pyrazolo[1,5-a] pyridine derivatives which will help them to design and synthesize potential compounds bearing this moiety.

Background: Zanthoxyli Bungeanum (ZB) has been reported to have an effect on lung carcinoma (LC). However, the defined pharmacological mechanism of ZB on LC has not been expounded completely because of the complicated ingredients.Objective: The aim of this work was to explore the active ingredients and mechanisms of ZB against LC by network pharmacology.Methods: In this study, systemic network pharmacology was used to explore the underlying mechanism of ZB, including pivotal components collection, target prediction, networks construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. At last, molecular docking was carried out to elucidate the involved pharmacological mechanisms.Results: Twenty-eight potential active compounds with 317 related targets and 598 LC-related targets were collected. Finally, 79 intersection targets were obtained use GO and KEGG pathway enrichment analyses. Based on component-target-pathway network, quercetin, β-sitosterol, and β- amyrin, and 6 targets were selected, including RAC-alpha serine/thre-onine-protein kinase (AKT1), mitogen-active protein kinase1 (MAPK1), Transcription factor p65 (RELA), Caspase-9 (CASP9), G1/S-specifi cyclin-D1 (CCND1), and PI3-kinase subunit gamma (PIK3CG); these six predicted targets were highly involved in the PI3K-AKT signaling pathway.Conclusion: The active ingredients and mechanisms of ZB against LC were firstly investigated using network pharmacology. This work provides scientific evidence to support the clinical effect of ZB on LC, new insights into the anti-LC mechanism of ZB, and guidance for further study.

Objective: This study aimed to evaluate the data according to five accepted criteria for the effects of twenty promising anticancer agents on five different cancer types and determine the most effective compounds for further in vitro and in vivo studies with a multi-criteria decision-making method (MCDM), which rationalizes decision making in a fuzzy environment to avoid the high cost and time requirements of further preclinical and clinical studies.Methods: Within the scope of the study, the weights of the five criteria were evaluated with the Pythagorean Fuzzy Analytic Hierarchy Process (PFAHP), which is one of the multi-criteria decisionmaking methods, and a comparison was made with the criteria weights obtained as a result of the Complex Proportional Assessment (COPRAS) method. Moreover, the effects of criteria weights calculated with PFAHP on evaluating alternatives were analyzed using different scenarios.Results: Experimentally, twenty N-heterocyclic quinoline derivatives with different substituents were identified as promising anticancer agents. In this study, the multi-criteria decision-making (MCDM) model was proposed to identify the most promising anticancer agents against all tested cell lines. Both the experimental and model results indicated that 20, 17, 19, and 7 are the most promising anticancer agents against the A549, HeLa, Hep3B, HT29, and MCF7 cell lines. Moreover, different scenarios were generated and analyzed to prove the consistency of the proposed methodology.Conclusion: MCDM strongly suggests that compounds 20, 17, 19, and 7 can be further investigated for in vivo studies.

Background: COVID-19 is caused by a novel strain of severe acute respiratory syndrome coronaviruses (SARS-CoV-2). It has claimed casualties around the world since the end of 2019 due to its high virulence and quick multiplicity in the human body. Hence, there has been a requirement to develop effective remedial measures to mitigate the mortality. Scientists have been able to develop corona vaccines to provide immunity, but there are no specific small-molecule chemotherapeutics to combat the novel coronavirus which has spread to the whole world due to its contagiousness. In the viral genome exploration, it has been found that the main protease, also known as chymotrypsin-like cysteine protease ([M^pro] or 3C-like protease [3CL^pro]) is responsible for the novel coronavirus replication, transcription, and host immunity destruction.Objectives: Therefore, the main protease has been selected as one of the major targets for the design of new inhibitors. The protein crystallographic and molecular docking studies on SARS-CoV-2 M^pro inhibitors and some quantitative structure-activity relationship (QSAR) studies have been carried out on SARSCoV main protease inhibitors to get some lead molecules for SARS-CoV-2 inhibition. However, there is hardly any QSAR done on the diverse data of SARS-CoV-2 main protease inhibitors. In view of it, QSAR studies have been attempted on SARS-CoV-2 M^pro inhibitors utilizing theoretical molecular descriptors solely computed from the structures of novel corona viral main protease inhibitors.Methods: As the number of structural descriptors is more than the observations, a genetic algorithm coupled with multiple linear methods has been applied for the development of QSAR models taking diverse SARS-CoV-2 M^pro inhibitors.Results: The developed best QSAR model showing R², Q² Loo, and R²pred values of 0.7389, 0.6666, and 0.6453 respectively has been further validated on an external data set where a good correlation (r = 0.787) has been found.Conclusion: Therefore, this model may be useful for the design of new SARS-CoV-2 main protease inhibitors.

Background: The increasing utilization of spiro compounds in drug discovery, led us to design and synthesize regioselectively some novel dispiroheterocycles, by a standard 1,3-dipolar cycloaddition reaction between 6-hydroxyaurone and in situ generated azomethine ylides, using ultra-sonication as green energy source. These results are first of its kind in the literature reported so far for the similar conditions. After confirmation of the proposed structures spectroscopically, using ¹H NMR, ¹³C NMR and FT-IR spectral data, all the compounds are screened for their potential biological activities.Methods: Three component protocol, that contain (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one, sarcosine and unsubstituted isatin. In which azomethine ylides react with olefinic dipolarophiles through 1,3-dipolar cycloaddition, which is highly regio- and stero-selective way in situ. Structures of the proposed products have been confirmed using ¹H NMR, ¹³C NMR and FT-IR spectral data.Results: In order to screen the potential biological activities of the synthesized compounds, their effect was observed on trypsin, amylase and lipase activities. Differential effect has been observed. Trypsin was substantially activated whereas an inhibitory effect was observed for amylase and lipase supported by in silico studies.Conclusion: Synthesis of six novel 6-hydroxy-1'-methyl-4'-phenyl-3H-dispiro[benzofuran-2,3'- pyrrolidine-2',3''-indoline]-2'',3-dione derivatives have been made using a multicomponent greener protocol. These synthesized compounds have exhibited differential effects toward trypsin, amylase and lipase well supported by in silico studies. Thus, the present study highlights their potential use as antiinflammatory and anti-obesity agents.

Background: This study aimed the determination of the antiproliferative and cytotoxic activities of recently prepared indeno [1,2-b]quinoline amines against colon carcinoma, HT29 and SW620 cell lines by using cell proliferation and cytotoxicity assays.Methods: In vitro inhibition of cell proliferation of indenoquinoline derivatives was determined with an MTT cell proliferation assay. On the other hand, their cell cytotoxicities and apoptotic potential were investigated by LDH cytotoxicity and DNA laddering assays. Moreover, molecular docking studies were performed between the compounds and PDB ID: 1OLG and 4LVT target proteins using virtual scanning techniques.Results: Most of the compounds (1, 3, and 7-9) exhibit much more potent antiproliferative activity than positive controls against HT29 and SW620 cell lines (IC50 values 1.1 - 4.1 μg/mL) and show slightly toxic properties (percent cytotoxicity 9.8% to 33.5%) to cells compared to positive control. On the other hand, it was determined that effective compounds 1, 2, 3 and 9 stimulated apoptosis on HT29 and SW620. Moreover, the anticancer effect of the recent indeno[1,2-b]quinoline amine derivatives was investigated with the help of molecular docking simulations for their pharmacokinetics. The molecular docking results displayed that mono bromo (1-3) and phenyl (7-9) substituted indeno [1,2-b]quinoline amines interact with mutated p53 and protein Blc-2 residues with hydrogen bonding and polar interactions, respectively.Conclusion: As a result, the preliminary experimental data and in silico studies indicated that the monosubstituted indenoquinoline amine derivatives, especially 1, 3, and 7-9, exhibit effective pharmacological properties.

Objective: Insulin resistance is a common link between diabetes mellitus (DM) and dementia. The current work emphasizes the effect of linagliptin on dementia with its neuroprotective effects, which occur directly at the neuronal level, as GLP-1 receptors are exclusively expressed in neurons.Methods: The objective of the study was to formulate linagliptin-loaded polymeric nanosuspension (LS) by nanoprecipitation method and further study their pharmaceutical, pharmacodynamics, scintigraphic, and neuroprotective effects following nose-to-brain delivery in the rat model of dementia.Results: Developed LS were spherical with z-average (250.7 nm), charge (-16.3 mV), % entrapment efficiency (95.8 ± 1.45%), and % drug loading (35.78 ± 0.19%). In vitro dissolution rate (88.56 ± 1.24%) and ex vivo permeation (81.59 ± 1.06%) of LS showed a better-sustained release profile than pure linagliptin. The spatial learning/memory in the treated group of Sprague-Dawley rats were significantly improved compared with those in the control group.Conclusion: Histopathological study of LS produced no toxicity or structural damage to the nasal mucosa. Optimum pharmaceutical characterization results improved pharmacodynamic studies/ histopathological data, and gamma-scintigraphic images proved that polymeric nanosuspensions stand out as wellappreciated approaches to deliver linagliptin more efficiently to the brain via intranasal route, thereby enhancing the neuroprotective efficacy in dementia.

Background: Liver cancer is a severe incurable disease and causes several thousands of deaths each year. Flavonoids are a class of bioactive compounds possessing anti-cancer activity.Objective: The objective of this study is to investigate the role of Buddleoside, one type of flavonoids, in carcinogenesis of liver cancer.Methods: Cell proliferation was detected by CCK-8 method, while cell invasion was by transwell assay, cell apoptosis by Annexin V/FITC-A staining. Western blotting technology was used to explore the mechanism of Buddleoside in liver cancer.Results: It was demonstrated that buddleoside inhibited cell proliferation in a dose-dependent manner and suppressed cell invasion in liver cancer. The inhibition rates of buddleoside in the invasion of both Huh-7 and Hep3B cells were above 75%. The apoptotic rates in the two cell lines were increased by about 10 folds in buddleoside group. Then, the expression levels of NFΚB/p65 and IKK were decreased when IΚB increased in buddleoside-treated Huh-7 cells, suggesting the inhibition of NFΚB signaling pathway. Moreover, the expression levels of cleaved caspase-3 and Bax were upregulated while HSDL2 decreased in buddleoside group. In contrast, after NFΚB/p65 was overexpressed, the expression patterns of these molecules were reversed partially. Consistently, the abilities of cell proliferation and cell invasion were recovered, while cell apoptosis decreased after NFΚB/p65 overexpression.Conclusion: Buddleoside inhibits proliferation, and invasion and induces apoptosis in liver cancer by regulating NFΚB signaling pathway. This study provides us with new proofs for the possible application of buddleoside in liver cancer therapy.

Introduction: Some microorganism threaten human health by forming biofilm in water systems. Because microorganism in the biofilm structure are more resistant to antimicrobials.Methods: Water systems are disinfected with physical methods, such as ultrasonication techniques and chemical disinfectants. Bromochloroacetonitrile is produced as a by-product from algae and fulvic acid sources during water chlorination. This study aimed to investigate the antimicrobial and antibiofilm effects of bromochloroacetonitrile on some bacteria alone and with ultrasound treatment. The study used Escherichia coli ATCC 25922, Klebsiella pneumoniae MCTC 13438, and Staphylococcus aureus ATCC 25923 strains. The antimicrobial and antibiofilm activities of the test substance were analyzed alone with bromochloroacetonitrile and Ultrasound-assisted. Minimum Inhibitory Concentration values of the test substance against Escherichia coli ATCC 25922, Klebsiella pneumoniae MCTC 13438, and Staphylococcus aureus ATCC 25923 strains were 25, 25 and 50 mM, respectively, and Minimum Bactericidal Concentration values were 50, >50, and >50 mM, respectively.Results: The obtained data show that bromochloroacetonitrile is a potential disinfection agent that can be used against biofilm formation in water systems. Besides, it was revealed that when ultrasound treatment was applied with bromochloroacetonitrile, it showed 100% antibiofilm activity on E. coli and K. pneumoniae and 79.45% antibiofilm activity on S. aureus strains. The obtained data show that bromochloroacetonitrile is a potential disinfection agent that can be used against biofilm formation in water systems. This study is preliminary and planned to reveal the cytotoxic effects of bromochloroacetonitrile on healthy human skin and liver cells in the following study.Conclusion: These results will contribute to the literature, as no study reveals the antimicrobial and antibiofilm activities of bromochloroacetonitrile.

Aims: This study aims to deduce the plausible contribution of polydatin in dopamine replenishment and dopaminergic neuroprotection to unveil its potential as a drug candidate for Parkinson's disease (PD).Background: Available therapies for the management of dopaminergic degradation in PD provide only symptomatic relief and are associated with various adverse effects. Levodopa (L-DOPA) is an age-old therapy in the treatment paradigm of PD, either used as mono-therapy or in combination with the inhibitors of the dopamine catabolising enzymes monoamine oxidase-B (MAO-B) and catechol-Omethyltransferase (COMT) for replenishing the levels of the neurotransmitter. The discovery of plantbased novel drug therapies would help to target multiple pathways underlying the disease pathogenesis and are associated with minimal side effects. Polydatin, the precursor of resveratrol, has been explored recently to possess neuroprotective efficacy, however, the molecular mechanisms that underlie the Parkinsonism- associated neurobehavioral recovery as well as the neurorescue potential of polydatin has not been illustrated yet.Objective: The present study aimed to unveil the role of polydatin in dopamine upregulation in PD, by determining its dual inhibitory potential on the enzymes responsible for its breakdown, MAO-B and COMT. The study further aimed to elucidate the role of this molecule in regulating the enzymatic activity of Cytosolic Phospholipase A2 (cPLA2), the crucial enzyme underlying several pathogenic pathways leading to neurodegeneration.Methods: Molecular docking simulation of polydatin with the dopamine catabolizing enzymes MAO-B and COMT, as well as cPLA2, along with their respective known inhibitors was performed using the Molegro Virtual Docker (MVD) 2.1 package.Results: In silico analyses revealed that polydatin could significantly inhibit the activities of this dopamine catabolizing enzyme, MAO-B and COMT with comparable docking scores and more numbers of hydrogen bonds, and weaker interactions as that of their respective available synthetic inhibitors. Moreover, it was found that polydatin could regulate the activity of cPLA2 comparable to its known inhibitor.Conclusion: Polydatin exhibited efficacy as a potent dopamine replenishing agent by inhibiting its metabolizing enzymes as well as found to have efficacy against neuroinflammation, thereby highlighting the significance of designing novel phyto drugs for combating dopamine deficiency in PD.

Background: Chemotherapy is regarded as first-line therapy in various cancer types besides surgical procedures. However, lack of cell selectivity and poor drug targeting to the cancer zone of the active agents results in accumulation in normal tissues with considerably high severe side effects. Therefore, novel drug delivery systems are required to enhance cancer treatment.Objective: In this study, Paclitaxel (PTX) incorporated Kollidon^® SR (KSR) and Chitosan (CS) based polymeric nanoparticles were prepared for potential use for colorectal cancer treatment.Methods: Polymeric nanoparticles were prepared by spray dying method. Physicochemical characterization studies were performed with particle size (PS), polydispersity index (PDI), zeta potential (ZP), drug loading (DL %), encapsulation efficiency (EE %) and structural evaluations using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (¹H-NMR) analyses. Cytotoxicity of the nanoparticles was screened on HT-29 (human colorectal adenocarcinoma) and HTC-15 (Dukes' type C, colorectal adenocarcinoma) cell lines with MTT assay.Results: Analysis results revealed the successful incorporation of PTX into the polymeric lattices. Particles showed cytotoxic activity on HT-29 and HTC-15 cell lines, depending on the application dose after 48 hours. Nanoparticles also remained stable at 5°C ± 3°C and 25°C ± 2°C (60% ± 5 Relative Humidity (RH)) during the storage period of 6 months.Conclusion: As a result of the study, KSR and CS-based nanoparticles could be regarded as promising nano-carriers for improved therapeutic efficacy of PTX for colorectal cancer treatment.