Microtubules are cylindrical protein polymers formed from
-tubulin heterodimers in the cytoplasm of eukaryotic cells. Microtubule disturbance may cause cell cycle arrest in the G2/M phase, and ...anomalous mitotic spindles will form. Microtubules are an important target for cancer drug action because of their critical role in mitosis. Several microtubule-targeting agents with vast therapeutic advantages have been developed, but they often lead to multidrug resistance and adverse side effects. Thus, single-target therapy has drawbacks in the effective control of tubulin polymerization. Molecular hybridization, based on the amalgamation of two or more pharmacophores of bioactive conjugates to engender a single molecular structure with enhanced pharmacokinetics and biological activity, compared to their parent molecules, has recently become a promising approach in drug development. The practical application of combined active scaffolds targeting tubulin polymerization inhibitors has been corroborated in the past few years. Meanwhile, different designs and syntheses of novel anti-tubulin hybrids have been broadly studied, illustrated, and detailed in the literature. This review describes various molecular hybrids with their reported structural-activity relationships (SARs) where it is possible in an effort to generate efficacious tubulin polymerization inhibitors. The aim is to create a platform on which new active scaffolds can be modeled for improved tubulin polymerization inhibitory potency and hence, the development of new therapeutic agents against cancer.
Some compounds reported as active against SARS CoV were selected, and docking studies were performed using the main protease of SARS CoV-2 as the receptor. The docked complex analysis shows that the ...ligands selectively bind with the target residues and binding affinity of amentoflavone (–10.1 kcal mol
), isotheaflavin-3’-gallate (–9.8 kcal mol
), tomentin A and D (–8.0 and –8.8 kcal mol
), theaflavin-3,3’-digallate (–8.6 kcal mol
), papyriflavonol A (–8.4 kcal mol
), iguesterin (–8.0 kcal mol
) and savinin (–8.3 kcal mol
) were ranked above the binding affinity of the reference, co-crystal ligand, ML188, a furan-2-carboxamide-based compound. To pinpoint the drug-like compound among the top-ranked compounds, the Lipinski’s rule of five and pharmacokinetic properties of all the selected compounds were evaluated. The results detailed that savinin exhibits high gastrointestinal absorption and can penetrate through the blood-brain barrier. Also, modifying these natural scaffolds with excellent binding affinity may lead to discovering of anti-SARS CoV agents with promising safety profiles.
A library of pyrazole–thiazolidinone conjugates was synthesized using a molecular hybridization approach through a Vilsmeier–Haack reaction. The compounds were tested for anti-microbial activity ...against two Gram-positive bacteria (
Staphylococcus aureus
and methicillin-resistant
Staphylococcus aureus
) and four Gram-negative bacteria (
Escherichia coli
,
Salmonella typhimurium
,
Klebsiella pneumonia
and
Pseudomonas aeruginosa
). Among the compounds tested
, 3
-
((2,4
-
dichlorophenyl)
-
1
-
(2,4
-
dinitrophenyl)
-
1H
-
pyrazol-yl)methylene)hydrazinecarbothioamide
(
3a
) and
2
-
((3
-
(2
-
chlorophenyl)
-
1
-
(2,4 dinitrophenyl)
-
1H
-
pyrazol
-
4
-
yl)methyleneamino)thiazolidin
-
4
-
on
e (
4b
) emerged as the most potent anti-microbial compounds with minimum bactericidal concentrations of < 0.2 µM against MRSA and
S. aureus
. Structure–activity relationship analysis further revealed that the presence of 2,4-dichloro moiety surprisingly influenced the activity of the compounds. Molecular docking studies of the compounds into the crystal structure of topoisomerase II and topoisomerase IV suggest that compounds
3a
and
4b
preferably interact with the targets through hydrogen bonding.
Heterocyclic compounds are a class of compounds of natural origin with favorable properties and hence have major pharmaceutical significance. They have an exceptional adroitness favoring their use as ...diverse smart biomimetics, in addition to possessing an active pharmacophore in a complex structure. This has made them an indispensable motif in the drug discovery field. Heterocyclic compounds are usually classified according to the ring size, type, and the number of heteroatoms present in the ring. Among different heterocyclic ring systems, nitrogen heterocyclic compounds are more abundant in nature. They also have considerable pharmacological significance. This review highlights recent pioneering studies in the biological assessment of nitrogen-containing compounds, namely: triazoles, tetrazoles, imidazole/benzimidazoles, pyrimidines, and quinolines. It explores publications between April 2020 and February 2022 and will benefit researchers in medicinal chemistry and pharmacology. The present work is organized based on the size of the heterocyclic ring.
A series of naphthalimide-chalcone/pyrazoline conjugates was prepared and evaluated for their anti-breast cancer potential against estrogen responsive,
MCF-7 (ER+), and triple-negative,
MDA-MB-231 ...(ER-), cell lines. The structure-activity-relationship (SAR) was deduced based on the influence of linker length, substituents on the phenyl ring and the generated functionalities, on anti-proliferative activities. Docking simulations further delineate the type of interactions of the designed molecules with the selected targets. This report discloses the scope of triazole tethered naphthalimide-chalcone/pyrazoline conjugates as anti breast cancer agents.
The use of medicinal plants in the treatment of malaria is gaining global attention due to their efficacy and cost effectiveness. This study evaluated the bioactivity-guided antiplasmodial efficacy ...and immunomodulatory effects of solvent fractions of Diospyros mespiliformis in mice infected with a susceptible strain of Plasmodium berghei (NK 65). The crude methanol extract of the stem of D. mespiliformis (DM) was partitioned between n-hexane, dichloromethane, ethyl acetate and methanol. Male Swiss mice (20 ± 2 g) infected with P. berghei were grouped and treated with vehicle (10 mL/kg, control), Artemether lumefantrine (10 mg/kg), 100, 200 and 400 mg/kg of n-hexane, dichloromethane, ethyl acetate and methanol fractions of D. mespiliformis for seven days. Blood was obtained for heme and hemozoin contents while serum was obtained for inflammatory cytokines and immunoglobulins G and M assessments. Liver mitochondria were isolated for mitochondrial permeability transition (mPT), mitochondrial F
F
ATPase (mATPase) and lipid peroxidation (mLPO) assays. The GC-MS was used to identify the compounds present in the most potent fraction. The dichloromethane fraction had the highest parasite clearance and improved hematological indices relative to the drug control. The heme values increased, while the hemozoin content significantly (P < 0.05) decreased compared with the drug control. The highest dose of HF and MF opened the mPT pore while the reversal effects of DF on mPT, mATPase and mLPO were dose-dependent. The levels of IgG, IgM and TNFα in the DF group were significantly higher than the drug control, while the IL-1β and IL-6 values did not vary linearly with the dose. Lupeol and Stigmastan-3,5-diene were the most abundant phytochemicals in the DF. The outcome of this study showed that the DF has immunomodulatory effects in infected mice, reduced proliferation of the malaria parasite and thus protect liver cells.
The RNA-dependent RNA polymerase (RdRp) receptor is an attractive target for treating human norovirus (HNV). A computer-aided approach like e-pharmacophore, molecular docking, and single point energy ...calculations were performed on the compounds retrieved from the Development Therapeutics Program (DTP) AIDS Antiviral Screen Database to identify the antiviral agent that could target the HNV RdRp receptor. Induced-fit docking (IFD) results showed that compounds ZINC1617939, ZINC1642549, ZINC6425208, ZINC5887658 and ZINC32068149 bind with the residues in the active site-B of HNV RdRp receptor via hydrogen bonds, salt bridge, and electrostatic interactions. During the molecular dynamic simulations, compounds ZINC6425208, ZINC5887658 and ZINC32068149 displayed an unbalanced backbone conformation with HNV RdRp protein, while ZINC1617939 and ZINC1642549 maintained stability with the protein backbone when interacting with the residues. Hence, the two new concluding compounds discovered by the computational approach can be used as a chemotype to design promising antiviral agents aimed at HNV RdRp.
Over the past two decades, it was discovered that introducing synthetic small interfering RNAs (siRNAs) into the cytoplasm facilitates effective gene-targeted silencing. This compromises gene ...expression and regulation by repressing transcription or stimulating sequence-specific RNA degradation. Substantial investments in developing RNA therapeutics for disease prevention and treatment have been made. We discuss the application to proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds to and degrades the low-density lipoprotein cholesterol (LDL-C) receptor, interrupting the process of LDL-C uptake into hepatocytes. PCSK9 loss-of-function modifications show significant clinical importance by causing dominant hypocholesterolemia and lessening the risk of cardiovascular disease (CVD). Monoclonal antibodies and small interfering RNA (siRNA) drugs targeting PCSK9 are a significant new option for managing lipid disorders and improving CVD outcomes. In general, monoclonal antibodies are restricted to binding with cell surface receptors or circulating proteins. Similarly, overcoming the intracellular and extracellular defenses that prevent exogenous RNA from entering cells must be achieved for the clinical application of siRNAs.
-acetylgalactosamine (GalNAc) conjugates are a simple solution to the siRNA delivery problem that is especially suitable for treating a broad spectrum of diseases involving liver-expressed genes. Inclisiran is a GalNAc-conjugated siRNA molecule that inhibits the translation of PCSK9. The administration is only required every 3 to 6 months, which is a significant improvement over monoclonal antibodies for PCSK9. This review provides an overview of siRNA therapeutics with a focus on detailed profiles of inclisiran, mainly its delivery strategies. We discuss the mechanisms of action, its status in clinical trials, and its prospects.
Benzimidazoles are fused heterocyclic ring systems containing two nitrogen atoms. They have vital therapeutic significance in drug discovery. Many clinically approved drugs have been developed from ...benzimidazole, and these include liarozole and pracinostat (anticancer), omeprazole (proton pump inhibitors), oxfendazole (Anthelmintic), enviroxine (antiviral), ilaprazole (antiulcer), ridinilazole (antibacterial), flubendazole (antiparasitic), bilastine (antihistaminic), and many more. The vast therapeutic applications of benzimidazole and its derivatives have propelled many researchers to develop more biologically active compounds bearing benzimidazole, thus broadening the scope of finding a remedy for other diseases; as a result, many new pharmaceutical drugs containing benzimidazole are expected to be available within the next decade. In this review, we describe bioactive benzimidazole hybrids in the recent year, from 2020 to 2022, to accentuate the pros of using benzimidazole in drug development.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed as the causative virus of COVID-19 disease, which is currently a worldwide pandemic. Efavirenz, a non-nucleoside reverse ...transcriptase inhibitor (NNRTI), is one of the most potent chemical compounds proposed to treat COVID-19 infection. We, therefore, performed virtual screening on FDA approved drugs that are similar to the efavirenz moiety. Subsequently, the compounds were subjected to screening by analyzing their drug-likeness, such as Lipinski's rule of five and ADMET properties. Molecular docking study revealed that Met165, His41, His163, and Phe140 were important interacting residues for COVID-19 main protease receptor-ligand interaction. Five top-ranked compounds, podophyllotoxin, oxacillin, lovastatin, simvastatin, and gefitinib, were selected by virtual screening and docking studies. The highest occupied molecular (HOMO) orbital, lowest unoccupied molecular orbital (LUMO) and energy gap values was calculated using density functional theory (DFT). The results of the study showed that lovastatin and simvastatin might be considered as lead compounds for further development for COVID-19 main protease inhibitors.
Pharmaceutical chemistry; Theoretical chemistry, COVID-19; NNRTI; Virtual screening; Efavirenz; HIV
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