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![Bioavailability Radars for selected IA-hybrids [31]. The pink area...](publication/345360240/figure/fig3/AS:1128651571626007@1646102912914/Bioavailability-Radars-for-selected-IA-hybrids-31-The-pink-area-represents-the-optimal_Q320.jpg)
In this paper, we report the synthesis of novel hybrids 2–14 based on itaconic acid and fluoroaniline, pyridine, indole and quinoline scaffolds. Itaconic acid is a naturally occurring compound with a Michael acceptor moiety, a key structural feature in several anticancer and antiviral drugs, responsible for the covalent binding of a drug to the cys...
Citations
... The 9-HHIA and 10-HHIA compounds were itaconic acid (IA) deriva tives with a C-C double bond and two carboxyl groups. It has been reported that IA is produced by a variety of microbes, including Aspergillus spp., and has been found to have a wide range of bioactivities including anti-bacterial, anti-inflammatory, and anticancer activities (23)(24)(25)(26). IA is also produced in mammalian macrophages and plays an important role as an anti-inflammatory and anti-bacterial metabolite (25,27,28). ...
Metallo-β-lactamases (MBLs) represent one of the main causes of carbapenem resistance in the order Enterobacterales. To combat MBL-producing carbapenem-resistant Enterobacterales, the development of MBL inhibitors can restore carbapenem efficacy for such resistant bacteria. Microbial natural products are a promising source of attractive seed compounds for the development of antimicrobial agents. Here, we report that hydroxyhexylitaconic acids (HHIAs) produced by a member of the genus Aspergillus can suppress carbapenem resistance conferred by MBLs, particularly IMP (imipenemase)-type MBLs. HHIAs were found to be competitive inhibitors with micromolar orders of magnitude against IMP-1 and showed weak inhibitory activity toward VIM-2, while no inhibitory activity against NDM-1 was observed despite the high dosage. The elongated methylene chains of HHIAs seem to play a crucial role in exerting inhibitory activity because itaconic acid, a structural analog without long methylene chains, did not show inhibitory activity against IMP-1. The addition of HHIAs restored meropenem and imipenem efficacy to satisfactory clinical levels against IMP-type MBL-producing Escherichia coli and Klebsiella pneumoniae clinical isolates. Unlike EDTA and Aspergillomarasmine A, HHIAs did not cause the loss of zinc ions from the active site, resulting in the structural instability of MBLs. X-ray crystallography and in silico docking simulation analyses revealed that two neighboring carboxylates of HHIAs coordinated with two zinc ions in the active sites of VIM-2 and IMP-1, which formed a key interaction observed in MBL inhibitors. Our results indicated that HHIAs are promising for initiating the design of potent inhibitors of IMP-type MBLs.
IMPORTANCE
The number and type of metallo-β-lactamase (MΒL) are increasing over time. Carbapenem resistance conferred by MΒL is a significant threat to our antibiotic regimen, and the development of MΒL inhibitors is urgently required to restore carbapenem efficacy. Microbial natural products have served as important sources for developing antimicrobial agents targeting pathogenic bacteria since the discovery of antibiotics in the mid-20th century. MΒL inhibitors derived from microbial natural products are still rare compared to those derived from chemical compound libraries. Hydroxyhexylitaconic acids (HHIAs) produced by members of the genus Aspergillus have potent inhibitory activity against clinically relevant IMP-type MBL. HHIAs may be good lead compounds for the development of MBL inhibitors applicable for controlling carbapenem resistance in IMP-type MBL-producing Enterobacterales.
... In the MCF-7 strain the IC50 (μM) was 50.10. Perković et al. [73] also investigated the antiproliferative activity of compounds containing the heterocyclic structures of pyridine, indole and quinoline against different tumor cell lines, including MCF-7, with GI50 values (μM) ranging from 2.0 ± 0.1 to 11.0 ± 0.3 for the MCF-7 strain, these results are like those found for the CAQA, CAIC and CAPA compounds. ...
... Considering the heterocycle CAQA (quinoline nucleus) at 0.5 μM, [73] was classified as a low-toxic compound with safe concentrations under 5 mg. L − 1 . ...
... [36][37][38] Itaconic acid has huge potential for broad researchers in medicine and other industries because of its safety, biological compatibility, microbial resistance, biodegradability, chemical reactivity, and also its anticancer properties. [38][39][40][41][42] Recently, the controlled/living radical polymerization has been investigated for itaconic acid monomer and its derivatives especially by using the reversible addition-fragmentation chain transfer (RAFT) process which is considered one of the easiest and most adaptable controlled/living radical polymerization systems due to its straightforward reaction procedure, broad range of applicable monomers, and high level of controllability. [43][44][45][46][47][48] In the current publication, a modified composite scaffold hydroxyapatite/hyperbranched polyitaconic acid/ chitosan (HAP/HBP-RAFT-PI/CS) was prepared. ...
... Every sample was repeated thrice and the average was taken. 42 ...
... 70 Moreover, HAP/HBP-RAFT-PI/CS showed higher cell viability than HAP-CS and CS in the fibroblast cell line indicating the increased biocompatibility of the scaffold due to the presence of HBP-RAFT-PI, but it showed lower viability in comparison to HAP-CS scaffold on cancer cell line due to the anticancer nature of itaconic acid. 40,42 The live/dead cell assay was done on MG63 cell line due to its higher cell viability and its similarity to osteoblast cells. The cellular growth of the MG63 cells were imaged by live/dead staining assay on day 2 as illustrated in Figure 8II. ...
In this study, a promising modified composite scaffold (hydroxyapatite/hyperbranched polyitaconic acid/chitosan) was synthesized for bone tissue engineering. Novel hyperbranched polyitaconic acid was prepared through the polymerization of itaconic acid using reversible addition fragmentation chain transfer using a macro‐RAFT agent. The chemical structure of the prepared hyperbranched polyitaconic acid was characterized by FTIR and ¹ HNMR and was subsequently embedded into hydroxyapatite/chitosan composite. The obtained modified composite scaffold was evaluated by characterizing its porosity, mechanical properties, bioactivity and cytotoxicity. The results showed that the modified composite scaffold had higher mechanical strength (i.e., 0.56 ± 0.03 MPa) in comparison to chitosan/hydroxyapatite scaffold only (i.e., 0.31 ± 0.01 MPa) and also showed higher bioactivity. In addition, the modified composite scaffold (HAP/HBP‐RAFT‐PI/CS) showed anticancer properties and enhanced human skin fibroblasts proliferation.
... As the global demand for IA is predicted to increase [16] and producers of IA derivatives with potential for industrial use have not yet been identified [10], the discovery of fungal producers of these compounds at a higher titer is desired. Interestingly, it is suggested that the terminal C-C double bond (C = C) in the vinylidene group of IA and its derivatives contributes to their biomonomeric and bioactive properties [11,17]. This implies that fungal producers of IA and its derivatives can be selectively isolated from nature using a detection method based on the terminal C = C structure. ...
Itaconic acid (IA) and its derivatives produced by fungi have significant potential as industrial feedstocks. We recently developed a method for the detection of these compounds based on their terminal C-C double bonds. However, the presence of reducing agents, such as glucose and other fungal metabolites, leads to undesirable side reactions, and consequently, deteriorates the detection specificity. Therefore, we developed a fluorescence detection method for IA and its derivatives underpinned by a photoclick reaction. The photoclick reaction between conjugated IA and 5-(4-methoxyphenyl)-2-phenyl-2H-tetrazole under UV irradiation affords a fluorescent product. No fluorescence was detected when succinic acid was subjected to the reaction, indicating that a terminal C-C double bond is required to induce fluorescence. Optimal reaction conditions were determined to be a combination of 80% final dimethyl sulfoxide concentration, 30-s UV irradiation, and a pH of 2. Two weeks after the reaction at 4 °C, 89.0% of the initial intensity was retained, indicating that the reaction product was relatively stable. Glucose and kojic acid did not induce fluorescence after the reaction, indicating that these reducing agents did not affect fluorescence. IA was detected in a culture of Aspergillus terreus, and its quantification using the photoclick reaction was in agreement with the results obtained using high-performance liquid chromatography analysis. Interestingly, the IA derivative avenaciolide present in submillimolar quantities was also detectable in a culture of Aspergillus avenaceus using this method. The established method will enable the development of high-throughput screening methods to identify fungi that produce IA and its derivatives.
... Chemical techniques generally create environmental problems and cause a reduction in fossils, whereas biological methods would decrease the environmental problems and lower the production cost and lead to sustainability [17]. Surprisingly, itaconic acid derivatives are a relatively unexplored area, with only a limited amount of information on their synthesis and/or biological activity available in the literature [18]. For example, the aliphatic copolyester poly [butylene fumarate-co-butylene itaconate] made from itaconic acid has exhibited modest anticancer activity against the MCF-7 adenocarcinoma cell line [19]. ...
Cancer is known as one of the dominant health diseases globally that threatens human health
and life. In the last few decades, the rate of infection and mortality due to different types of cancer has
risen. Itaconic acid (IA) is an organic acid with distinct structure and properties, including numerous
organic acids. Its applications have been developed in biomedical areas, such as ophthalmic acid, dental
care, and drug delivery fields. Our research work is intended to identify the anticancer property of
itaconic acid. This study employed about 58 cancer proteins for molecular docking analysis and
molecular dynamic simulation studies. Molecular docking studies predict that the itaconic acid
compound showed good binding affinity to anticancer proteins. The compound (IA) has an excellent
binding affinity with binding energies of -11.26 and -6.99 kcal/mol 1A2B and 1JFF proteins. Furthur
MD stimulation was employed to identify compounds as hit compounds. The compound IA is discussed
in this article, and its anticancer activities against cancer proteins are documented. The theoretical study
information strongly revealed that itaconic acid could be used to develop future target drugs against
death-causing diseases like cancer.
... Several research articles present novel and multifaceted techniques for antimicrobial polymer production based on this renewable monomer, IA [137,[145][146][147]. A proficient and effective biobased polymer was produced through radical homopolymerization and copolymerization by integrating pendant alkyne groups in the IA's carboxylic acids structure, resulting in interactive IA derivatives. ...
... As described previously, IA can be converted into drug-delivery systems, different hydrogels in water treatment and analyses, intelligent food packaging, antimicrobial polymers, or even in cleaning products, adhesives, coatings, thickeners, fibers, binders, lipase immobilization [160], and many other applications [101]. Additionally, IA and its derivatives have anti-inflammatory [161] antitumor [145] and antimicrobial activities [147,162], which could be further maneuvered therapeutically for inflammatory disorder treatment. ...
... IA derivate cationic antimicrobial copolymer (adapted after[145]). ...
Intense research has been conducted to produce environmentally friendly biopolymers obtained from renewable feedstock to substitute fossil-based materials. This is an essential aspect for implementing the circular bioeconomy strategy, expressly declared by the European Commission in 2018 in terms of "repair, reuse, and recycling". Competent carbon-neutral alternatives are renewable biomass waste for chemical element production, with proficient recyclability properties. Itaconic acid (IA) is a valuable platform chemical integrated into the first 12 building block compounds the achievement of which is feasible from renewable biomass or bio-wastes (agricultural, food by-products, or municipal organic waste) in conformity with the US Department of Energy. IA is primarily obtained through fermentation with Aspergillus terreus, but nowadays several microorganisms are genetically engineered to produce this organic acid in high quantities and on different substrates. Given its trifunctional structure, IA allows the synthesis of various novel biopolymers, such as drug carriers, intelligent food packaging, antimicrobial biopolymers, hydrogels in water treatment and analysis, and superabsorbent polymers binding agents. In addition, IA shows antimicrobial, anti-inflammatory, and antitumor activity. Moreover, this biopolymer retains qualities like environmental effectiveness, biocompatibility, and sustainability. This manuscript aims to address the production of IA from renewable sources to create a sustainable circular economy in the future. Moreover, being an essential monomer in polymer synthesis it possesses a continuous provocation in the biopolymer chemistry domain and technologies, as defined in the present review.
In our continuous effort to develop novel antiepileptic drug, a new series of nipecotic acid derivatives having1,3,4-thiadiazole nucleus were designed and synthesized. This study aims to improve the lipophilicity of nipecotic acid by attaching some lipophilic anchors like thiadiazole and substituted aryl acid derivatives. In our previous study, we noticed that the N-substituted oxadiazole derivative of nipecotic acid exhibited significant antiepileptic activity in the rodent model. The synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, Mass, and elemental analysis. The anticonvulsant activity was evaluated by using the maximal electroshock-induced seizure model in rats (MES) and the subcutaneous pentylenetetrazol (scPTZ) test in mice. None of the compounds were found to be active in the MES model whereas compounds (TN2, TN9, TN12, TN13, and TN15) produced significant protection against the scPTZ-induced seizures model. The compounds showing antiepileptic activity were additionally evaluated for antidepressant activity by using the forced swim test, 5-hydroxytryptophan (5-HTP)-induced head twitch test, and learned helplessness test. All the molecules that showed anticonvulsant activity (TN2, TN9, TN12, TN13, and TN15), also exerted significant antidepressant effects in the animal models. The selected compounds were subjected to different toxicity studies. Compounds were found to have no neurotoxicity in the rota-rod test and devoid of hepatic and renal toxicity in 30 days repeated oral toxicity test. Further, a homology model was developed to perform the in-silico molecular docking and dynamics studies which revealed the similar binding of compound TN9 within the active binding pocket and were found to be the most potent anti-epileptic agent. The market expectation for newly developed antiepileptic thiadiazole-based nipecotic acid derivatives is significant, driven by their potential to offer improved therapeutic outcomes and reduced side effects, addressing a critical need in epilepsy treatment. These innovative compounds hold promise for meeting the demand for more effective and safer antiepileptic medications.
Hexahydroquinoline (HHQ) scaffold was constructed and recruited for development of new series of anticancer agents. Thirty-two new compounds were synthesised where x-ray crystallography was performed to confirm enantiomerism. Thirteen compounds showed moderate to good activity against NCI 60 cancer cell lines, with GI % mean up to 74% for 10c. Expending erlotinib as a reference drug, target compounds were verified for their inhibiting activities against EGFRWT, EGFRT790M, and EGFRL858R where compound 10d was the best inhibitor with IC50 = 0.097, 0.280, and 0.051 µM, respectively, compared to erlotinib (IC50 = 0.082 µM, 0.342 µM, and 0.055 µM, respectively). Safety profile was validated using normal human lung (IMR-90) cells. 10c and 10d disrupted cell cycle at pre-G1 and G2/M phases in lung cancer, HOP-92, and cell line. Molecular docking study was achieved to understand the potential binding interactions and affinities in the active sites of three versions of EGFRs.
Insect cell-baculovirus expression vector system is one of the most established platforms to produce biological products, and it plays a fundamental role in the context of COVID-19 emergency, providing recombinant proteins for treatment, diagnosis, and prevention. SARS-CoV-2 infection is mediated by the interaction of the spike glycoprotein trimer via its receptor-binding domain (RBD) with the host’s cellular receptor. As RBD is required for many applications, in the context of pandemic it is important to meet the challenge of producing a high amount of recombinant RBD (rRBD). For this reason, in the present study, we developed a process based on Sf9 insect cells to improve rRBD yield. rRBD was recovered from the supernatant of infected cells and easily purified by metal ion affinity chromatography, with a yield of 82% and purity higher than 95%. Expressed under a novel chimeric promoter (polh-pSeL), the yield of rRBD after purification was 21.1 ± 3.7 mg/L, which is the highest performance described in Sf9 cell lines. Finally, rRBD was successfully used in an assay to detect specific antibodies in COVID-19 serum samples. The efficient strategy herein described has the potential to produce high-quality rRBD in Sf9 cell line for diagnostic purpose.
