Since its first report in December 2019, the novel coronavirus virus, SARS-CoV-2, has caused an unprecedented global health crisis and economic loss imposing a tremendous burden on the worldwide ...finance, healthcare system, and even daily life. Even with the introduction of different preventive vaccines, there is still a dire need for effective antiviral therapeutics. Nature has been considered as the historical trove of drug discovery and development, particularly in cases of worldwide crises. Herein, a comprehensive
in silico
investigation of a highly focused chemical library of 34 pederin-structurally related marine compounds, belonging to four polyketides families, was initiated against the SARS-CoV-2 main protease, Mpro, being the key replicating element of the virus and main target in many drugs development programs. Two of the most potent SARS-CoV-2 Mpro co-crystallized inhibitors, O6K and N3, were added to the tested database as reference standards. Through molecular docking simulation, promising compounds including Pederin (
1
), Dihydro-onnamide A (
11
), Onnamide C (
14
), Pseudo-onnamide A (
17
), and Theopederin G (
29
) have been identified from different families based on their superior ligand-protein energies and relevant binding profiles with the key Mpro pocket residues. Thermodynamic behaviors of the identified compounds were investigated through 200 ns all-atom molecular dynamics simulation illustrating their significant stability and pocket accommodation. Furthermore, structural activity preferentiality was identified for the pederin-based marine compounds highlighting the importance of the terminal guanidine and cyclic hemiacetal linker, and the length of the sidechain. Our findings highlight the challenges of targeting SARS-CoV-2 Mpro as well as recommending further
in vitro
and
in vivo
studies regarding the examined marine products either alone or in combination paving the way for promising lead molecules.
Marine natural polyketides showed promising SARS-CoV-2 main protease inhibitory activities.
Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase involved in diverse fundamental cellular processes such as apoptosis and autophagy. DAPK1 isoform plays an essential ...role as a tumor suppressor and inhibitor of metastasis. Consequently, DAPK1 became a promising target protein for developing new anti-cancer agents. In this work, we present the rational design and complete synthetic routes of a novel series of eighteen aryl carboxamide derivatives as potential DAPK1 inhibitors. Using a custom panel of forty-five kinases, a single dose of 10 µM of the picolinamide derivative 4a was able to selectively inhibit DAPK1 kinase by 44.19%. Further investigations revealed the isonicotinamide derivative 4q as a promising DAPK1 inhibitory lead compound with an IC50 value of 1.09 µM. In an in vitro anticancer activity assay using a library of 60 cancer cell lines including blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers, four compounds (4d, 4e, 4o, and 4p) demonstrated high anti-proliferative activity with mean % GI ~70%. Furthermore, the most potent DAPK1 inhibitor (4q) exhibited remarkable activity against leukemia (K-562) and breast cancer (MDA-MB-468) with % GI of 72% and 75%, respectively.
The continuing need for the discovery of potent antibacterial agents against antibiotic-resistant pathogens is the driving force for many researchers to design and develop such agents. Herein, we ...report the design, synthesis, and biological evaluation of amidine derivatives as new antibacterial agents. Compound
was the most active in this study against a wide range of antibiotic-resistant, and susceptible, Gram-positive, and Gram-negative bacterial strains. Time-kill assay experiments indicated that compound
was an effective bactericidal compound against the tested organisms at the log-phase of bacterial growth. Docking simulations were performed to assess
its mode of action regarding UPPS, KARI, and DNA as potential bacterial targets. Results unveiled the importance of structural features of compound
in its biological activity including central thiophene ring equipped with left and right pyrrolo2,3-
pyridine and phenyl moieties and two terminal amidines cyclized into 4,5-dihydro-1
-imidazol-2-yl functionalities. Collectively, compound
represents a possible hit for future development of potent antibacterial agents.
Direct growth inhibition of infectious organisms coupled with immunomodulation to counteract the immunosuppressive environment might be a beneficial therapeutic approach. Herein, a library of ...sulfuretin analogs were developed with potential capabilities to inhibit production of the immunosuppressive PGE2 and elicit direct growth inhibition against Leishmania donovani; the major causative agent of the fatal visceral leishmaniasis. Amongst explored library members bearing diverse methoxy and/or hydroxy substitution patterns at rings B and A, analog 1i retaining the C6-hydroxy moiety at ring-A, but possessing methoxy moieties in place of the polar dihydroxy moieties of sulfuretin ring-B, as well as analog 1q retaining the sulfuretin′s polar dihydroxy moieties at ring-B, but incorporating a C6-methoxy moiety instead of the C6-hydroxy moiety at ring-A, were the most promising hit compounds. Cytotoxicity evaluation suggested that analog 1i possesses a safety profile inducing the death of the parasite rather than host cells. In silico simulation provided insights into their possible binding with Leishmania donovani fumarate reductase. The current investigation presents sulfuretin analogs 1i and 1q as potential hit compounds for further development of multifunctional therapeutic agents against visceral leishmaniasis.
Several arylamide-based antiproliferative agents are known and some of them are currently FDA-approved anticancer drugs. Provoked by the need to fill the existing room with new drugs, 31 compounds ...constituting a series of flavone-based arylamide derivatives were synthesized and biologically evaluated. Towards extensive evaluation, sixty diverse cancer cell lines representing nine cancer diseases of various origins have been used for evaluation of their efficacy, spectrum and potency. Two compounds 2aw and 2ax emerged as effective, broad-spectrum and potent anticancer agents that outperformed masitinibt and imatininb, which are FDA-approved anticancer drugs. Kinases profiling as possible targets for the potent compound 2aw showed that it might be a hit compound offering a starting point to develop inhibitors of STE20/GCK-IV kinase family members including HGK, TNIK and MINK1 kinases. Mechanistic study showed that compounds 2aw triggers cell cycle arrest in HT29 colon cancer cells. In conclusion, this work presents compound 2aw as a new broad-spectrum anticancer agent for further development of promising treatment of diverse cancers.
Broad-spectrum and high potency of compounds 2aw and 2ax against nine cancer diseases. Display omitted
•Synthesis and in vitro antiproliferative activities of 31 flavone-based arylamide derivatives.•2aw and 2ax elicit broad-spectrum anticancer activity with potency that outperformed masitinibt and imatininb; FDA-approved anticancer drugs.•2aw is a hit GCK-IV kinase inhibitor offering novel starting point to develop new GCK-IV inhibitors.•The antiproliferative activity of 2aw in HT29 colon cancer cells is mediated through G1-cell cycle arrest.
Most fungal bone and joint infections (arthritis) are caused by Mucormycosis (
). These infections may be difficult to treat and may lead to chronic bone disorders and disabilities, thus the use of ...new antifungal materials in bone disorders is vital, particularly in immunocompromised individuals, such as those who have contracted coronavirus disease 2019 (COVID-19). Herein, we reported for the first time the preparation of nitrogen-doped carbon quantum dots (N/CQDs) and a nitrogen-doped mesoporous carbon (N/MC) using a quick micro-wave preparation and hydrothermal approach. The structure and morphology were analysed using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and surface area analyser. Minimum inhibitory concentration (MIC), disc diffusion tests, minimum fungicidal concentration (MFC) and antifungal inhibitory percentages were measured to investigate the antifungal activity of N/CQDs and N/MC nanostructures. In addition to the
antifungal activity in rats as determined by wound induction and infection, pathogen count and histological studies were also performed. According to
and
testing, both N/CQDs with small size and N/MC with porous structure had a significant antifungal impact on a variety of bone-infecting bacteria, including Mucor infection. In conclusion, the present investigation demonstrates that functional N/CQDs and N/MC are effective antifungal agents against a range of microbial pathogenic bone disorders in immunocompromised individuals, with stronger and superior fungicidal activity for N/CQDs than N/MC
and
studies.
Hybridization of reported weakly active antiproliferative hit 5-amino-4-pyrimidinol derivative with 2-anilino-4-phenoxypyrimidines suggests a series of 2,5-diamino-4-pyrimidinol derivatives as ...potential antiproliferative agents. Few compounds belonging to the proposed series were reported as CSF1R/DAPK1 inhibitors as anti-tauopathies. However, the correlation between CSF1R/DAPK1 signalling pathways and cancer progression provides motives to reprofile them against cancer therapy. The compounds were synthesised, characterized, and evaluated against M-NFS-60 cells and a kinase panel which bolstered predictions of their antiproliferative activity and suggested the involvement of diverse molecular targets. Compound 6e, the most potent in the series, showed prominent broad-spectrum antiproliferative activity inhibiting the growth of hematological, NSCLC, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers by 84.1, 52.79, 72.15, 66.34, 66.48, 51.55, 55.95, 61.85, and 60.87%, respectively. Additionally, it elicited an IC
50
value of 1.97 µM against M-NFS-60 cells and good GIT absorption with P
e
value of 19.0 ± 1.1 × 10
−6
cm/s (PAMPA-GIT). Molecular docking study for 6e with CSF1R and DAPK1 was done to help to understand the binding mode with both kinases. Collectively, compound 6e could be a potential lead compound for further development of anticancer therapies.
Nanotechnology holds substantial promise in the innovative therapies for rheumatoid arthritis (RA). The current study was designed to synthesize and characterize a new graphene titanate nanocomposite ...(GTNc) and explore its anti-arthritic, anti-inflammatory, and antioxidant potencies against Complete Freund’s adjuvant (CFA)-induced arthritis in rats, as well as investigate the underlying molecular mechanisms. Our characterization methods included XRD, FT-IR, SEM, EDX, zeta potential, practical size, and XRF to characterize the novel GTNc. Our findings revealed that arthritic rats treated with GTNc exhibited lower levels of RF, CRP, IL-1β, TNF-α, IL-17, and ADAMTS-5, and higher levels of IL-4 and TIMP-3. In arthritic rats, GTNc reduced LPO levels while increasing GSH content and GST antioxidant activity. Additionally, GTNc decreased the expression of the TGF-β mRNA gene in arthritic rats. Histopathological investigation showed that GTNc reduced inflammatory cell infiltration, cartilage degradation, and bone destruction in joint injuries caused by CFA in the arthritic rats. Collectively, the anti-arthritic, anti-inflammatory, and antioxidant properties of GTNc appear promising for future arthritis treatments and bone disability research.
CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers that ...affect humans worldwide. The available therapeutic options suffer from many drawbacks including high toxicity and decreased specificity. Therefore, there is a need for more effective and safer therapeutic agents. A series of new pyrazolo3,4-dpyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo3,4-dpyrimidinone derivatives bearing N5-2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds 4a and 4b confirmed their CDK2 inhibitory activity. Compound 4a was more potent than the reference roscovitine regarding the CDK2 inhibitory activity (IC50 values: 0.21 and 0.25 µM, respectively). In silico molecular docking provided insights into the molecular interactions of compounds 4a and 4b with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds 4a and 4b were identified as interesting CDK2 inhibitors eliciting antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for future further investigations and development.
Wound healing is a significant healthcare problem that decreases the patient’s quality of life. Hence, several agents and approaches have been widely used to help accelerate wound healing. The ...challenge is to search for a topical delivery system that could supply long-acting effects, accurate doses, and rapid healing activity. Topical forms of simvastatin (SMV) are beneficial in wound care. This study aimed to develop a novel topical chitosan-based platform of SMV with folic acid (FA) for wound healing. Moreover, the synergistic effect of combinations was determined in an excisional wound model in rats. The prepared SMV-FA-loaded films (SMV-FAPFs) were examined for their physicochemical characterizations and morphology. Box-Behnken Design and response surface methodology were used to evaluate the tensile strength and release characteristics of the prepared SMV-FAPFs. Additionally, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction pattern (XRD), and animal studies were also investigated. The developed SMV-FAPFs showed a contraction of up to 80% decrease in the wound size after ten days. The results of the quantitative real-time polymerase chain reaction (RT-PCR) analysis demonstrated a significant upregulation of dermal collagen type I (CoTI) expression and downregulation of the inflammatory JAK3 expression in wounds treated with SMV-FAPFs when compared to control samples and individual drug treatments. In summary, it can be concluded that the utilization of SMV-FAPFs holds great potential for facilitating efficient and expeditious wound healing, hence presenting a feasible substitute for conventional topical administration methods.
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