Aims
Flavonoids and related compounds, such as quercetin‐based antiviral drug Gene‐Eden‐VIR/Novirin, inhibit the protease of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The ...alkylated chalcones isolated from Angelica keiskei inhibit SARS‐CoV proteases. In this study, we aimed to compare the anti‐SARS CoV‐2 activities of both newly synthesized chalcone derivatives and these two drugs.
Methods
Determination of the potent antiviral activity of newly synthesized chalcone derivatives against SARS‐CoV‐2 by calculating the RT‐PCR cycling threshold (Ct) values.
Results
Antiviral activities of the compounds varied because of being dose dependent. Compound 6, 7, 9, and 16 were highly effective against SARS‐CoV‐2 at the concentration of 1.60 µg/mL. Structure‐based virtual screening was carried out against the most important druggable SARS‐CoV‐2 targets, viral RNA‐dependent RNA polymerase, to identify putative inhibitors that could facilitate the development of potential anti‐coronavirus disease‐2019 drug candidates.
Conclusions
Computational analyses identified eight compounds inhibiting each target, with binding affinity scores ranging from −4.370 to −2.748 kcal/mol along with their toxicological, ADME, and drug‐like properties.
An important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide ...benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7-48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC
12.62 nM for AChE and IC
25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values of - 7.29 kcal/mol for AChE and - 6.71 kcal/mol for BChE (whereas donepezil was - 6.49 kcal/mol and - 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 Å) and BChE (average RMSD: 2.2 Å) (donepezil had average RMSD: 1.65 Å and 2.7 Å, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents.
Cholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimer's disease. Azole antifungals have come under the spotlight with recent discoveries ...that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC50 values were obtained for imidazole derivatives, which were further tested and found potent competitive cholinesterase inhibitors via enzyme kinetics study. The active derivatives showed negligible toxicity in in vitro cytotoxicity tests. Molecular modeling studies predicted that these derivatives were druglike, could penetrate blood‐brain barrier, and tightly bind to cholinesterase active site making key interactions via the imidazole moiety at protonated state. Thus, current study identifies potent and competitive cholinesterase inhibitor azoles with minor toxicity and potential to pass into the central nervous system.
Enzyme inhibition is a very active area of research in drug design and development. Chalcone derivatives have a broad enzyme inhibitory activity and function as potential molecules in the development ...of new drugs. In this study, the synthesized novel halogenated chalcones with bromobenzyl and methoxyphenyl moieties were evaluated toward the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and human erythrocyte carbonic anhydrase I (hCA I), and II (hCA II) isoenzymes. They showed highly potent inhibition ability toward AChE with Ki values of 1.83 ± 0.21–11.19 ± 0.96 nM and BChE with Ki values of 3.35 ± 0.91–26.70 ± 4.26 nM; hCA I with Ki values of 29.41 ± 3.14–57.63 ± 4.95 nM, and hCA II with Ki values of 24.00 ± 5.39–54.74 ± 1.65 nM. Among the tested enzyme inhibitions, compounds 14 and 13 were the most active compounds against AChE and BChE. Docking studies were performed to the most active compounds against AChE, BChE, hCA I and hCA II to propose a binding mode in the active site and molecular dynamics simulations were studied to check the molecular interactions and the stability of the ligands in the active site. The results may contribute to the development of new drugs particularly to treat some global disorders including Alzheimer’s disease (AD), glaucoma, and diabetes.
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•New halogenated chalcones were synthesized.•Their structures were elucidated by IR NMR, and elemental analysis.•Some halogenated chalcones displayed highly potent inhibition ability toward AChE, BChE, hCA I and II.•Putative binding modes were proposed, and molecular dynamics simulations were performed.
Irinotecan and topotecan are derivatives of the naturally occurring cytotoxic compound camptothecin that are used in the treatment of patients with colorectal cancer, either as single agents or in ...combination with radiotherapy and/or other chemotherapy drugs. They are inhibitors of DNA topoisomerase I (Top I) and exert their cytotoxic effects in replicating cells by inducing DNA strand breaks. A wide range of DNA repair proteins is involved in the recognition and repair of these breaks, and depletion or inhibition of some of these proteins increases the cytotoxic effects of Top I inhibitors. Building on these laboratory observations, ongoing translational research is aiming to establish whether this mechanistic information can be used to improve the treatment of patients with certain types of cancer. Two potential strategies are under investigation: (1) individualising treatment by evaluating levels and/or patterns of expression of DNA repair proteins that predict clinical response to Top I inhibitors, and (2) developing small molecule inhibitors of these repair enzymes to overcome tumour resistance and improve outcomes. This review summarises the current status of these research endeavours, focusing on the key roles of tyrosyl DNA phosphodiesterase 1 (Tdp1) and poly(ADP-ribose) polymerase (PARP), and examines the pre-clinical and clinical data that support the potential value of these and other DNA repair proteins as predictive markers and therapeutic targets. Since irinotecan is increasingly being combined with radiotherapy, the potential for these proteins to act as predictive biomarkers for both Top I inhibitors and radiation is proposed, and the possibility of synergistic potentiation of chemoradiation regimes by Tdp1 and/or PARP inhibitors is considered.
Fourteen novel Chalcone‐Cu complexes were effectively synthesized in this work. The newly synthesized Chalcone‐Cu complexes were assessed for their effects on human carbonic anhydrase isoenzymes I ...and II, acetylcholinesterase enzymes, and antioxidant activity. The intricate compounds exhibited Ki values ranging from 41.65–190.42 nM against hCA I, 15.79–259.07 nM against hCA II, and 14.36–175.73 nM against AChE enzymes. These complexes demonstrated potent inhibitory profiles against the specified metabolic enzymes, surpassing the inhibitory effects of acetazolamide (for hCA I and II) and tacrine (for AChE). The antioxidant properties of the compounds were assessed using DPPH and ABTS radical scavenging assays, revealing that the complexes had moderate to high efficacy in neutralizing free radicals. All complexes underwent molecular docking experiments. Compounds 14, 22, and 23 yielded the highest docking scores. Compound 14 demonstrated a docking score of −6.414 kcal/mol against hCAI, whereas compound 23 attained a docking score of −6.697 kcal/mol against hCA II. Compound 22 exhibited the most favorable docking score of −9.645 kcal/mol against AChE. The acquired results have the potential to help towards the development of new drugs containing Cu complex structures for the treatment of prevalent ailments such as glaucoma and Alzheimer's diseases.
This study unveils the potential of Chalcone‐Cu complexes as potent enzyme inhibitors (hCA I and II and AChE) with antioxidant properties. The structural insights, inhibitory profiles, and molecular docking results underscore their therapeutic potential for neurological disorders. The findings present a foundation for further exploration and drug development in the realm of Chalcone‐Cu compounds.
Azoles are first-line drugs used in fungal infections. Topical antifungals, such as miconazole and econazole, are known to be active against Gram-positive bacteria, which was reported to result from ...bacterial flavohemoglobin (flavoHb) inhibition. Dual antibacterial/antifungal action is believed to have benefits for antimicrobial chemotherapy. In this study, we tested antibacterial effects of an in-house library of naphthalene-bearing azoles, some of which were reported as potent antifungals, in an attempt to find dual-acting hits. Several potent derivatives were obtained against the Gram-positive bacteria, Enterococcus faecalis and Staphylococcus aureus. 9 was active at a minimum inhibitor concentration (MIC) less than 1 µg/ml against E. faecalis and S. aureus, and 10 against S. aureus. 16 was also potent against E. faecalis and S. aureus (MIC = 1 and 2 µg/ml, respectively). Six more were active against S. aureus with MIC ≤ 4 µg/ml. In vitro cytotoxicity studies showed that the active compounds were safe for healthy cells within their MIC ranges. According to the calculated descriptors, the library was found within the drug-like chemical space and free of pan-assay interference compounds (PAINS). Molecular docking studies suggested that the compounds might be bacterial flavohemoglobin (flavoHb) inhibitors and the azole and naphthalene rings were important pharmacophores, which was further supported by pharmacophore modeling study. As a result, the current study presents several non-toxic azole derivatives with antibacterial effects. In addition to their previously reported antifungal properties, they could set a promising starting point for the future design of dual acting antimicrobials.
Communicated by Ramaswamy H. Sarma
Gluteal artery perforator flaps have gained popularity due to reliability, preservation of the muscle, versatility in flap design without restricting other flap options, and low donor-site morbidity ...in ambulatory patients and possibility of enabling future reconstruction in paraplegic patients. But the inconstant anatomy of the vascular plexus around the gluteal muscle makes it hard to predict how many perforators are present, what their volume of blood flow and size are, where they exit the overlying fascia, and what their course through the muscle will be. Without any prior investigations, the reconstructive surgeon could be surprised intraoperatively by previous surgical damage, scar formation, or anatomic variants.For these reasons, to confirm the presence and the location of gluteal perforators preoperatively we have used color Doppler ultrasonography. With the help of the color Doppler ultrasonography 26 patients, 21 men and 5 women, were operated between the years 2002 and 2007. The mean age of patients was 47.7 (age range: 7-77 years). All perforator vessels were marked preoperatively around the defect locations. The perforator based flap that will allow primary closure of the donor site and the defect without tension was planned choosing the perforator that showed the largest flow in color Doppler ultrasonography proximally. Perforators were found in the sites identified with color Doppler ultrasonography in all other flaps. In our study, 94.4% flap viability was ensured in 36 perforator-based gluteal area flaps. Mean flap elevation time was 31.9 minutes. We found that locating the perforators preoperatively helps to shorten the operation time without compromising a reliable viability of the perforator flaps, thus enabling the surgeon easier treatment of pressure sores.
The split-thickness skin graft (STSG) donor sites have been treated with various and plenty of dressing techniques and materials. An ideal STSG donor site dressing should have antibacterial, ...hemostatic, and promoting epidermal healing properties. We have performed a prospective study to evaluate the effect of the oxidized regenerated cellulose on STSG donor site healing. Between January 2002 and January 2005, 40 patients who were operated in any kind of reconstructive operations with STSG donor sites were included in the study. One half of the wound was covered with oxidized regenerated cellulose and the other half of the same wound of the same patient was covered with fine mesh gauze treated with Furacin (nitrofurazone). The patients were grouped into 2 depending on the dressing technique: group I, semiclosed and group II, closed. The wounds were evaluated for healing time, infection, pain perception of the patient, and final esthetic results. The oxidized regenerated cellulose side of the group I was healed in a mean of 6.5 +/- 0.51 days; in group II, 5.4 +/- 0.50 days (range, 5-6 days). The fine mesh gauze treated with Furacin in group I was healed in a mean of 9.9 +/- 0.97 days (range, 8-11 days); in group II, 8.4 +/- 0.99 days (range, 7-10 days). There was a statistical significance between the oxidized regenerated cellulose side and the fine mesh gauze side (P < 0.001) in group I and group II separately. The difference between group I and group II was statistically significant in the oxidized regenerated cellulose side (P < 0.001), and the difference between group I and group II was statistically significant in the fine mesh gauze side (P < 0.005). The antibacterial, hemostatic, and absorbable property of the oxidized regenerated cellulose could ensure the utilization as an alternative STSG donor site dressing, especially because the positive influence over the wound healing was proven.
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