ADME in silico

In this study, we designed two series of novel anthraquinone-based benzenesulfonamide derivatives and their analogues as potential carbonic anhydrase inhibitors (CAIs) and evaluated their inhibitory activities against off-target human carbonic anhydrase II (hCA II) isoform and tumor-associated human carbonic anhydrase IX (hCA IX) isoform. Most of these compounds exhibited good inhibitory activities against hCA II and IX. The compounds that exhibited the best hCA inhibition were further studied against the MDA-MB-231, MCF-7, and HepG2 cell lines under hypoxic and normoxic conditions...

Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II ( h CA I and h CA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE...

Series of 7-(Trifluoromethyl) substituted indolizine 4a-g was synthesized using the one-pot method. Spectroscopic techniques such as IR, 1 H-NMR, 13 C-NMR, and HRMS were used for the structure confirmation of newly synthesized compounds. These 4a-g compounds were tested for their anti-inflammatory activity. In this study, we identified novel indolizine derivative compounds 4a-g selectively targeting COX-2 enzyme, tumor necrosis factor-α (TNF-α) and, interleukin-6 (IL-6). The in silico docking studies of 4a-g showed that these compounds have a higher affinity for COX-2 enzyme, TNF- α, and IL-6...

The COVID-19 pandemic caused by the SARS-CoV-2 virus, recognized by the World Health Organization (WHO), has led to 164,523,894 confirmed cases and 3,412,032 deaths globally as of May 20, 2021. SARS-CoV-2 encodes crucial proteases for its replication cycle, including the papain-like protease (PLpro), presenting a potential target for developing COVID-19 treatments. Mauritine, a cyclopeptide alkaloid found in the Ziziphus-spina christi plant, exhibits antiviral properties and was investigated for its affinity and toxicity towards PLpro using molecular docking through MGLTools 1...

The current pharmacotherapies for Alzheimer's disease (AD) demonstrate limited efficacy and are associated with various side effects, highlighting the need for novel therapeutic agents. Natural products, particularly from medicinal plants, have emerged as a significant source of potential neuroprotective compounds. In this context, Cissampelos capensis L.f., renowned for its medicinal properties, has recently yielded three new proaporphine alkaloids; cissamaline, cissamanine, and cissamdine. Despite their promising bioactive profiles, the biological targets of these alkaloids in the context of AD have remained unexplored...

In this study, we designed, synthesized, and evaluated a series of 1,2,4-triazole benzimidazoles for their cytotoxic effects against the A549, C6, and NIH3T3 cell lines. Additionally, these compounds were assessed for their inhibitory activity against DNA topoisomerase I, aiming to develop novel anticancer agents. The synthesized final compounds 4a - h were characterized using 1 H NMR, 13 C NMR, and HRMS. Among them, compounds 4b and 4h emerged as the most potent agents against the A549 cell line, exhibiting an IC50 value of 7...

Acridines are a class of bioactive agents which exhibit high biological stability and the ability to intercalate with DNA; they have a wide range of applications. Pyridine derivatives have a wide range of biological activities. To enhance the properties of acridine and 2-amino-3-methylpyridine as the active pharmaceutical ingredient (API), 4-nitrobenzoic acid was chosen as a coformer. In the present study, a mixture of acridine and 4-nitrobenzoic acid forms the salt acridinium 4-nitrobenzoate, C13 H10 N+ ·C7 H4 NO4 - (I), whereas a mixture of 2-amino-3-methylpyridine and 4-nitrobenzoic acid forms the salt 2-amino-3-methylpyridinium 4-nitrobenzoate, C6 H9 N2 + ·C7 H4 NO4 - (II)...

In this study, we designed and synthesized a number of novel 1,2,3-triazole-piperazin-benzo[ b ][1,4]thiazine 1,1-dioxide derivatives and investigated their in vitro antibacterial and hemolytic activity. When compared to the lead chemical, dicloxacillin, the majority of the compounds demonstrated acceptable activity. Among them, the most promising compounds 6e, 6g, 6i, 8d, and 8e exhibited excellent antibacterial activity against the methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), and vancomycin-resistant S...

Medicinally valuable components derived from natural resources are highly desirable as prospective alternatives to synthetic drugs to treat fatal diseases, such as cancer and diabetes mellitus. Suaeda maritima (L.) Dumort ( Amaranthaceae ) ( S. maritima ) is a halophyte plant that can thrive in saline environments and possesses excellent medicinal properties. Hence, for the present investigation, S. maritima has been chosen, and its phytochemical constituents have been extracted utilizing various solvents, including hexane, acetone, and methanol, and identified by GC-MS, LC-MS, and HPLC analyses...

Alzheimer's disease (AD) is a multifactorial irreversible neurological disorder with multiple enzymes involved. In the treatment of AD, multifunctional agents targeting cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have shown promising results. Herein, a series of novel quinoline-sulfonamides (a1-18) were designed and synthesized as a dual inhibitor of MAOs and ChEs. The in vitro results showed that compounds a5, a12, a11, and a6 exhibited the most potent compounds against specific enzymes. They had IC50 value 0...

Membrane permeability is an in vitro parameter that represents the apparent permeability (Papp) of a compound, and is a key absorption, distribution, metabolism, and excretion parameter in drug development. Although the Caco-2 cell lines are the most used cell lines to measure Papp, other cell lines, such as the Madin-Darby Canine Kidney (MDCK), LLC-Pig Kidney 1 (LLC-PK1), and Ralph Russ Canine Kidney (RRCK) cell lines, can also be used to estimate Papp. Therefore, constructing in silico models for Papp estimation using the MDCK, LLC-PK1, and RRCK cell lines requires collecting extensive amounts of in vitro Papp data...

Pain and anesthesia are a problem for all physicians. Scientists from different countries are constantly searching for new anesthetic agents and methods of general anesthesia. In anesthesiology, the role and importance of local anesthesia always remain topical. In the present work, a comparative analysis of the results of pharmacological studies on models of the conduction and terminal anesthesia, as well as acute toxicity studies of the inclusion complex of 1-methyl-4-ethynyl-4-hydroxypiperidine (MEP) with β-cyclodextrin, was carried out...

A new series of thieno[2,3- d ][1,2,4]triazolo[1,5- a ]pyrimidines was designed and synthesized using readily available starting materials, specifically, β -enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 μM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 μM)...

Globally, lung cancer is a significant public health concern due to its role as the leading cause of cancer-related mortalities. The promising target of EGFR for lung cancer treatment has been identified, providing a potential avenue for more effective therapies. The purpose of the study was to design a library of 1843 coumarin-1,2,3-triazole hybrids and screen them based on a designed pharmacophore to identify potential inhibitors targeting EGFR in lung cancer with minimum or no side effects. Pharmacophore-based screening was carried out and 60 hits were obtained...

Cancer's global impact necessitates innovative and less toxic treatments. Thiosemicarbazones (TSCs), adaptable metal chelators, offer such potential. In this study, we have synthesized N (4)-substituted heterocyclic TSCs from syringaldehyde (TSL1, TSL2), and also report the unexpected copper-mediated cyclization of the TSCs to form thiadiazoles (TSL3, TSL4), expanding research avenues. This work includes extensive characterization and studies such as DNA/protein binding, molecular docking, and theoretical analyses to demonstrate the potential of the as-prepared TSCs and thiadiazoles against different cancer cells...

Latest studies confirmed that abnormal function of histone deacetylase (HDAC) plays a pivotal role in formation of tumors and is a potential therapeutic target for treating breast cancer. In this research, in-silico drug discovery approaches via quantitative structure activity relationship (QSAR) and molecular docking simulations were adapted to 43 compounds of indazole derivatives with HDAC inhibition for anticancer activity against breast cancer. The QSAR models were built from multiple linear regression (MLR), and models predictability was cross-validated by leave-one-out (LOO) method...

The global surge in Alzheimer's disease poses a significant public health concern. In response, we study the efficacy of carnosic acid and related abietane-type diterpenes extracted from rosemary as acetylcholinesterase (AChE) inhibitors. Our analyses, using in silico techniques, encompassed all the compounds within this extract. Through molecular docking, we explored how these compounds interact with the active site of the AChE protein. The docking scores, ranging from -5.560 Kcal/mol to -7.270 Kcal/mol, indicate robust binding affinities...

The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and in vivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For in vivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software...

In this study, we present a novel series of (E)-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-((E)-(((Z)-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) through the formation of hydrogen bonds with the pivotal active site Cys387 residue. Their effectiveness against the M. tuberculosis H37Rv strain was examined and notably, three compounds (namely T4, T7, and T12) exhibited promising antitubercular activity, with a minimum inhibitory concentration (MIC) of 1...

Targeting pro-inflammatory cytokines and their production is found to be of therapeutic benefit for the regulation of inflammation in various chronic autoimmune diseases. Our continued efforts to discover small molecular-weight pro-inflammatory cytokine inhibitors resulted in identifying a novel natural lignan molecule named polonilignan, isolated from the culture broth extract of an endophytic fungus Penicillium polonicum. An in silico study (molecular docking, ADME predictions, binding free energy calculation and molecular dynamics simulation) of the polonilignan over the pro-inflammatory cytokines proteins TNF-α, IL-6 and IL-1β was performed using Schrodinger LLC software to understand the binding interactions, drug-like properties, and stability of the ligand-protein complex...