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1.
BMC Chem ; 18(1): 132, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39014447

ABSTRACT

The search for new molecules targeting SARS-CoV-2 has been a priority since 2020. The continuous evolution of new mutants increases the need for more research in the area. One way to find new leads is to repurpose existing drugs and molecules against the required target. Here, we present the in vitro and in silico screening of ten previously synthesized and reported compounds as anti-COVID 19 agents. The compounds were screened in vitro against VERO-E6 cells to find their Cytotoxic Concentration (CC50) and their Inhibitory Concentration (IC50). Compounds 1, 2, and 5 revealed a promising anti-SARS-CoV-2 of (IC50 = 2.4, 11.2 and 2.8 µM), respectively while compounds 3 and 7 showed moderate activity of (IC50 = 17.8 and 26.1 µM) compared to Chloroquine which showed an IC50 of 24.9 µM. Among tested compounds, 1 showed the highest selectivity (CC50/IC50) of 192.8. Docking, molecular dynamics and ADME studies were done to investigate potential interactions between compounds and SARS-CoV-2 targets as well as to study the possibility of using them as lead compounds.

2.
Biomolecules ; 13(10)2023 09 26.
Article in English | MEDLINE | ID: mdl-37892134

ABSTRACT

In light of the COVID-19 global pandemic caused by SARS-CoV-2, ongoing research has centered on minimizing viral spread either by stopping viral entry or inhibiting viral replication. Repurposing antiviral drugs, typically nucleoside analogs, has proven successful at inhibiting virus replication. This review summarizes current information regarding coronavirus classification and characterization and presents the broad clinical consequences of SARS-CoV-2 activation of the angiotensin-converting enzyme 2 (ACE2) receptor expressed in different human cell types. It provides publicly available knowledge on the chemical nature of proposed therapeutics and their target biomolecules to assist in the identification of potentially new drugs for the treatment of SARS-CoV-2 infection.


Subject(s)
COVID-19 , Humans , SARS-CoV-2/metabolism , Peptidyl-Dipeptidase A/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Virus Internalization
3.
Molecules ; 28(18)2023 Sep 13.
Article in English | MEDLINE | ID: mdl-37764378

ABSTRACT

The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease quickly spreads due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties and computer-aided drug design (in silico studies) for optimizing anti-SARS-CoV-2 hits/leads.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Pandemics , Disease Outbreaks , Indoles/pharmacology , Indoles/therapeutic use
4.
Curr Res Toxicol ; 5: 100118, 2023.
Article in English | MEDLINE | ID: mdl-37609475

ABSTRACT

Herbal medications have an extensive history of use in treating various diseases, attributed to their perceived efficacy and safety. Traditional medicine practitioners and contemporary healthcare providers have shown particular interest in herbal syrups, especially for respiratory illnesses associated with the SARS-CoV-2 virus. However, the current understanding of the pharmacokinetic and toxicological properties of phytochemicals in these herbal mixtures is limited. This study presents a comprehensive computational analysis utilizing novel approach methodologies (NAMs) to investigate the pharmacokinetic and toxicological profiles of phytochemicals in herbal syrup, leveraging in-silico techniques and prediction tools such as PubChem, SwissADME, and Molsoft's database. Although molecular dynamics, docking, and broader system-wide analyses were not considered, future studies hold potential for further investigation in these areas. By combining drug-likeness with molecular simulation, researchers identify diverse phytochemicals suitable for complex medication development examining their pharmacokinetic-toxicological profiles in phytopharmaceutical syrup. The study focuses on herbal solutions for respiratory infections, with the goal of adding to the pool of all-natural treatments for such ailments. This research has the potential to revolutionize environmental and alternative medicine by leveraging in-silico models and innovative analytical techniques to identify novel phytochemicals with enhanced therapeutic benefits and explore network-based and systems biology approaches for a deeper understanding of their interactions with biological systems. Overall, our study offers valuable insights into the computational analysis of the pharmacokinetic and toxicological profiles of herbal concoction. This paves the way for advancements in environmental and alternative medicine. However, we acknowledge the need for future studies to address the aforementioned topics that were not adequately covered in this research.

5.
J Enzyme Inhib Med Chem ; 38(1): 2185761, 2023 Dec.
Article in English | MEDLINE | ID: mdl-36912230

ABSTRACT

Hepatocellular carcinoma is considered one of the most lethal cancers, which is characterised by increasing prevalence associated with high level of invasion and metastasis. The novel synthetic pyrazolo[3,4-b]pyridine compound, WRH-2412, was reported to exhibit in vitro antitumor activity. This study was conducted to evaluate the antitumor activity of WRH-2412 in HCC induced in rats through affecting the TGF-ß/ß-catenin/α-SMA pathway. Antitumor activity of WRH-2412 was evaluated by calculating the rat's survival rate and by assessment of serum α-fetoprotein. Protein expression of TGF-ß, ß-catenin, E-cadherin, fascin and gene expression of SMAD4 and α-SMA were determined in hepatic tissue of rats. WRH-2412 produced antitumor activity by significantly increasing the rats' survival rate and decreasing serum α-fetoprotein. WRH-2412 significantly reduced an HCC-induced increase in hepatic TGF-ß, ß-catenin, SMAD4, fascin and α-SMA expression. In addition, WRH-2412 significantly increased hepatic E-cadherin expression.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Rats , Animals , Carcinoma, Hepatocellular/pathology , Transforming Growth Factor beta/metabolism , beta Catenin/metabolism , Catenins , alpha-Fetoproteins , Liver Neoplasms/pathology , Cadherins/genetics , Cadherins/metabolism , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism
6.
Molecules ; 27(18)2022 Sep 12.
Article in English | MEDLINE | ID: mdl-36144662

ABSTRACT

We synthesized a set of small molecules using a molecular hybridization approach with good yields. The antiviral properties of the synthesized conjugates against the SAR-CoV-2 virus were investigated and their cytotoxicity was also determined. Among all the synthesized conjugates, compound 9f showed potential against SARS-CoV-2 and low cytotoxicity. The conjugates' selectivity indexes (SIs) were determined to correlate the antiviral properties and cytotoxicity. The observed biological data were further validated using computational studies.


Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Antiviral Agents/therapeutic use , Humans , Molecular Docking Simulation
7.
Sci Rep ; 12(1): 13880, 2022 08 16.
Article in English | MEDLINE | ID: mdl-35974029

ABSTRACT

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.


Subject(s)
Antineoplastic Agents , COVID-19 Drug Treatment , Spiro Compounds , Antineoplastic Agents/chemistry , Cell Line, Tumor , Humans , Indoles , Molecular Structure , SARS-CoV-2 , Spiro Compounds/chemistry , Spiro Compounds/pharmacology
8.
Pharmaceuticals (Basel) ; 15(2)2022 Feb 03.
Article in English | MEDLINE | ID: mdl-35215303

ABSTRACT

The development of new antibiotics to treat multidrug-resistant (MDR) bacteria or possess broad-spectrum activity is one of the challenging tasks. Unfortunately, there are not many new antibiotics in clinical trials. So, the molecular hybridization approach could be an effective strategy to develop potential drug candidates using the known scaffolds. We synthesized a total of 31 diverse linezolid conjugates 3, 5, 7, 9, 11, 13, and 15 using our established benzotriazole chemistry with good yield and purity. Some of the synthesized conjugates exhibited promising antibacterial properties against different strains of bacteria. Among all the synthesized compounds, 5d is the most promising antibacterial agent with MIC 4.5 µM against S. aureus and 2.25 µM against B. subtilis. Using our experimental data pool, we developed a robust QSAR (R2 = 0.926, 0.935; R2cvOO = 0.898, 0.915; R2cvMO = 0.903, 0.916 for the S. aureus and B. subtilis models, respectively) and 3D-pharmacophore models. We have also determined the drug-like properties of the synthesized conjugates using computational tools. Our findings provide valuable insight into the possible linezolid-based antibiotic drug candidates.

9.
Eur J Med Chem ; 227: 113952, 2022 Jan 05.
Article in English | MEDLINE | ID: mdl-34731763

ABSTRACT

In the current study, we report on the development of novel series of pyrazolo[3,4-b]pyridine derivatives (8a-u, 11a-n, and 14a,b) as potential anticancer agents. The prepared pyrazolo[3,4-b]pyridines have been screened for their antitumor activity in vitro at NCI-DTP. Thereafter, compound 8a was qualified by NCI for full panel five-dose assay to assess its GI50, TGI and LC50 values. Compound 8a showed broad-spectrum anti-proliferative activities over the whole NCI panel, with outstanding growth inhibition full panel GI50 (MG-MID) value equals 2.16 µM and subpanel GI50 (MG-MID) range: 1.92-2.86 µM. Furthermore, pyrazolo[3,4-b]pyridines 8a, 8e-h, 8o, 8u, 11a, 11e, 11h, 11l and 14a-b were assayed for their antiproliferative effect against a panel of leukemia cell lines (K562, MV4-11, CEM, RS4;11, ML-2 and KOPN-8) where they possessed moderate to excellent anti-leukemic activity. Moreover, pyrazolo[3,4-b]pyridines 8o, 8u, 14a and 14b were further explored for their effect on cell cycle on RS4;11 cells, in which they dose-dependently increased populations of cells in G2/M phases. Finally we analyzed the changes of selected proteins (HOXA9, MEIS1, PARP, BcL-2 and McL-1) related to cell death and viability in RS4;11 cells via Western blotting. Collectively, the obtained results suggested pyrazolo[3,4-b]pyridines 8o, 8u, 14a and 14b as promising lead molecules for further optimization to develop more potent and efficient anticancer candidates.


Subject(s)
Antineoplastic Agents/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
10.
Cells ; 8(7)2019 06 29.
Article in English | MEDLINE | ID: mdl-31261948

ABSTRACT

Neuroinflammation and microglia-mediated neurotoxicity contribute to the pathogenesis of a broad range of neurodegenerative diseases; therefore, identifying novel compounds that can suppress adverse activation of glia is an important goal. We have previously identified a class of trisubstituted pyrazoles that possess neuroprotective and anti-inflammatory properties. Here, we describe a second generation of pyrazole analogs that were designed to improve their neuroprotective activity toward neurons under inflammatory conditions. Pyrazolyl oxalamide derivatives were designed to explore the effects of steric and electronic factors. Three in vitro assays were performed to evaluate the compounds' anti-neurotoxic, neuroprotective, and cytotoxic activity using human THP-1, PC-3, and SH-SY5Y cells. Five compounds significantly reduced the neurotoxic secretions from immune-stimulated microglia-like human THP-1 monocytic cells. One of these compounds was also found to protect SH-SY5Y neuronal cells when they were exposed to cytotoxic THP-1 cell supernatants. While one of the analogs was discarded due to its interference with the cell viability assay, most compounds were innocuous to the cultured cells at the concentrations used (1-100 µM). The new compounds reported herein provide a design template for the future development of lead candidates as novel inhibitors of neuroinflammation and neuroprotective drugs.


Subject(s)
Microglia/drug effects , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/pharmacology , Neurotoxicity Syndromes/drug therapy , Pyrazoles/pharmacology , Cell Survival/drug effects , Culture Media/toxicity , Drug Evaluation, Preclinical , Humans , Microglia/pathology , Monocytes , Neurodegenerative Diseases/pathology , Neuroprotective Agents/chemical synthesis , Neurotoxicity Syndromes/pathology , Pyrazoles/chemical synthesis , THP-1 Cells
11.
Curr Pharm Des ; 22(11): 1546-57, 2016.
Article in English | MEDLINE | ID: mdl-26795564

ABSTRACT

Bone metastasis is one of the most common causes of skeletal morbidity in patients with advanced cancer and is manifested as osteoblastic and osteolytic lesions. Bone metastasis occurs as an organized and multistep process involving tumor intravasation and the survived tumor cells in circulation. Extravasation into the secondary site, initiation of tumorgenesis and angiogenesis are also included in developing the bone metastasis. Several studies demonstrated that Zoledronic acid, which belongs to the second generation of BP (nitrogen-containing BPs) class agents, is an important and well-established drug in the treatment of wide range of cancer patients, such as breast cancer, prostate cancer, and multiple myeloma associated with bone metastases.


Subject(s)
Bone Neoplasms/drug therapy , Bone Neoplasms/physiopathology , Bone Resorption/prevention & control , Diphosphonates/therapeutic use , Animals , Bone Neoplasms/secondary , Humans
12.
Eur J Med Chem ; 57: 362-72, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23124162

ABSTRACT

A general synthetic approach to two new series of methylenebisphosphonates: arylamino-2-ethane-1,1-diyl- and benzoxazole-2-methylenebisphosphonates is presented. Acid hydrolysis of selected BPs was undertaken to give the corresponding bisphosphonic acid (BP-acid). Next, the prediction of the permeability (hydrophobicity) of the target compounds was measured, by a combination of RP-HPLC and computational techniques, to study the capacity of transporting the molecule through cellular membranes. Cytotoxicity/growth inhibition of 50% (GI(50), mg/L) and antichronic inflammation properties of the products were evaluated. Later on, a comparison of the pharmacological results with water-octanol partition coefficients (log K(OW)) of the compounds was also reported.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antineoplastic Agents/chemical synthesis , Benzoxazoles/chemical synthesis , Cytotoxins/chemical synthesis , Diphosphonates/chemical synthesis , Hypersensitivity, Delayed/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Benzoxazoles/pharmacology , Cell Line, Tumor , Cell Membrane/metabolism , Cytotoxins/pharmacology , Diphosphonates/pharmacology , Female , Humans , Hydrolysis , Hydrophobic and Hydrophilic Interactions , Hypersensitivity, Delayed/chemically induced , Inflammation/chemically induced , Inflammation/drug therapy , Inhibitory Concentration 50 , Male , Mice , Octanols , Permeability , Serum Albumin, Bovine , Solubility , Water
13.
Arch Pharm (Weinheim) ; 345(11): 884-95, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22930562

ABSTRACT

Carbodiimide that was generated from the condensation reaction of iminophosphorane with phenylisocyanate was allowed to react with different phosphorus nucleophiles. Thus, the in situ resulted heterocumulene reacted with dialkylhydrogenphosphonates in tetrahydrofuran (THF)/FeCl(3) /H(2) O system to give fused pyrrole- (≈14%) and pyrimidinephosphonates (≈57%). On the other hand, with tris-(dialkyl)aminophosphines, the reaction afforded the corresponding hexaalkylphosphinic diamides as a water-sensitive fine powder, quite stable for a few days in a desiccator. When a protonating agent was present in the reaction medium, the reaction was markedly accelerated leading to the formation of the phosphamides. Next, some saturated and unsaturated Horner-Emmons reagents were applied in situ to the same carbodiimide to obtain more phosphorylated N-heterocycles. The analgesic and antiinflammatory activities of the newly synthesized compounds were investigated and showed significant activities. Finally, we further estimated the antitumor activity of five new phosphonates against four carcinoma cell lines.


Subject(s)
Carbodiimides/pharmacology , Organophosphonates/pharmacology , Peptidomimetics/pharmacology , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carbodiimides/chemical synthesis , Carbodiimides/chemistry , Cell Line, Tumor , Disease Models, Animal , Drug Stability , Humans , Inflammation/drug therapy , Male , Mice , Neoplasms/drug therapy , Neoplasms/pathology , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Pain/drug therapy , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Structure-Activity Relationship
14.
Org Biomol Chem ; 7(16): 3319-30, 2009 Aug 21.
Article in English | MEDLINE | ID: mdl-19641791

ABSTRACT

A new class of C-glycosyl amino acids displaying a thiourea segment as a linker has been designed and synthesized by addition of peracetylated glycosylmethyl isothiocyanates to an amine-functionalized amino acid (N(alpha)-Fmoc-beta-amino-l-alanine). Three pairs of compounds with alpha- and beta-galacto, alpha- and beta-gluco, and alpha- and beta-manno configuration have been prepared with yields ranging between 70 and 75%. The orthogonal set of protective groups (O-acetyl in the carbohydrate moiety and N-Fmoc in the amino acid residue) makes these compounds suitable substrates for the co-translational modification of natural peptides. The couplings of model hydroxy-free and perbenzylated glycosylmethyl isothiocyanates with the above N(alpha)-Fmoc-beta-amino-l-alanine and the N(alpha)-Boc-protected analogue have been carried out as well, thus broadening the scope of the coupling reaction. Nevertheless, there are limitations of this isothiocyanate-amine coupling in complex systems, and these are briefly discussed.


Subject(s)
Amines/chemistry , Amino Acids/chemistry , Protein Modification, Translational , Alanine/chemistry , Amino Acids/chemical synthesis , Carbohydrates/chemistry , Combinatorial Chemistry Techniques , Isothiocyanates/chemistry , Stereoisomerism , Structure-Activity Relationship , Thiourea/chemistry
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