Sürdürülebilir Kalkınma Amaçları
Yayınlar
- MakaleAçık Erişim2026Scopus SJRQ2Rhodanine–Sulfonate hybrids targeting aldose reductase: Synthesis, in vitro inhibition, molecular docking, and cytotoxicity studies
Kalay, Erbay; Demir, Yeliz; Türkeş, Cüneyt; Aslan, Osman Nuri; Pezik, Esra; Şahin, Engin
Aldose reductase (ALR2), a key enzyme in the polyol pathway, plays a significant role in the onset and progression of diabetic complications, rendering it a critical pharmacological target. In this study, a novel series of twenty-four sulfonate ester-functionalized rhodanine derivatives (compounds 1–24) were rationally designed, synthesized via Knoevenagel condensation, and comprehensively evaluated for their inhibitory activity against ALR2. Spectroscopic and spectrometric methods confirmed the structural integrity of the synthesized compounds. In vitro enzyme inhibition assays revealed that all compounds acted as competitive inhibitors, with several analogues, particularly compounds 6 and 8, exhibiting stronger ALR2 inhibition (Ki = 0.43 µM and 0.48 µM, respectively) than the reference drug epalrestat (Ki = 0.98 µM). Structure–activity relationship (SAR) analysis highlighted the critical influence of para-substituted electron-donating (e.g., methyl) and electron-withdrawing (e.g., nitro, halogen) groups on binding potency. Molecular docking of the most potent inhibitor (compound 6) demonstrated a stable binding pose supported by key interactions, including hydrogen bonding with His110 and π–π stacking with Phe122. In silico ADME profiling confirmed favorable drug-likeness properties for all derivatives. Cytotoxicity studies on L929, A549, and RG-2 cell lines revealed that most compounds were less toxic than the reference drug at lower concentrations, with compound 8 showing a promising cytotoxic profile. These findings position rhodanine–sulfonate hybrids as promising scaffolds for the development of next-generation ALR2 inhibitors for the treatment of diabetic complications.
AtıfScopus2WoS3
İncele - MakaleAçık Erişim2025Scopus SJRQ1Design, synthesis, and inhibition of α-glucosidase by novel L-phenylalanine-derived hydrazones: Kinetic, molecular docking, and dynamics studies
Kalay, Erbay; Adem, Şevki; Demir, Yeliz; Aslan, Osman Nuri; Şahin, Engin; Eyupoglu, Volkan; Rawat, Ravi; Çomaklı, Veysel
In this paper, a series of novel hydrazones derived from L-phenyl alanine were synthesized in four steps and employed to inhibit α-glucosidase through kinetic studies, molecular docking, and molecular dynamics analyses. Among the synthesized compounds, 8, 15, and 16 exhibited the strongest inhibitory effects, with IC50 values of 31.08 μM, 24.15 μM, and 19.47 μM, respectively, surpassing the standard inhibitor acarbose (79.63 μM). Molecular docking studies revealed robust interactions, with compound 16 achieving the highest MolDock score of −176.316. Molecular dynamics simulations were conducted to evaluate the binding affinity of compound 16 to the isomaltase enzyme from Saccharomyces cerevisiae (3A4A). The most favorable docking pose was subjected to further analysis through MD simulations under dynamic conditions. The MMGBSA analysis of the simulation cluster indicated a strong binding affinity of approximately −43.06 kcal/mol, highlighting the compound's potential for modulating α-glucosidase activity. These results underscore the potential of bromine and hydroxyl-substituted hydrazones to modulate isomaltase activity, with therapeutic implications for hyperglycemia and obesity management.
AtıfScopus12WoS12OpenAlex16İncele - MakaleAçık Erişim2024Scopus SJRQ3Optimization of asymmetric bioreduction conditions of 1-indanone by Leuconostoc mesenteroides N6 using a face-centered design-based multi-objective optimization model
Alamoudi, Mohammed; Özdemir, Akın; Dertli, Enes; Bolubaid, Mohammed; Alidrisi, Hassan M.; Taylan, Osman; Yılmaz, Mustafa Tahsin; Şahin, Engin
There has been an increasing interest in biocatalysts over the past few decades in order to obtain high efficiency, high yield, and environmentally benign procedures aiming at the manufacture of pharmacologically relevant chemicals. Lactic Acid Bacteria (LAB), a microbial group, can be employed as biocatalysts while performing asymmetric reduction of prochiral ketones. In this study, Leuconostoc mesenteroides N6 was used for the asymmetric bioreduction 1-indanone. And then, a novel and innovative face-centered design-based multi-objective optimization model was used to optimize experimental conditions. Also, the experimental design factors were defined as agitation speed, incubation period, pH, and temperature for optimization to acquire the maximum enantiomeric excess (ee) and conversion rate (cr) values. When using the face-centered design-based multi-objective optimization model, the optimum culture conditions corresponded to 96.34 and 99.42%, ee and cr responses, respectively, were pH = 5.87, incubation temperature = 35 °C, incubation period = 50.88 h, and agitation speed = 152.60 rpm. Notably, the validation experiment under the optimum model conditions confirmed the model results. This study demonstrated the importance of the optimization and the efficiency of the face-centered design-based multi-objective model.
AtıfScopus1WoS9OpenAlex1İncele - MakaleAçık Erişim2024Scopus SJRQ1Efficient bioreduction of 4-phenyl-2-butanone to drug precursor (S)-4-phenyl-2-butanol by a whole-cell biocatalyst using a novel hybrid design technique
Bayhan, Beyzanur; Özdemir, Akın; Dertli, Enes; Şahin, Engin
Asymmetric synthesis is a critical tactic in pharmaceutical industries for creating chiral medications as it allows an enantiomer to be obtained in synthetic chemistry. The asymmetric bioreduction processes by biocatalysts have shown significant potential in producing chiral alcohols. The amount of substrate and the production method of the biocatalytic synthesis of (S)-4-phenyl-2-butanol ((S)-2) are not still desired levels. Furthermore, the biocatalytic asymmetric reduction of 4-phenyl-2-butanone (1) to (R)- or (S)-4-phenyl-2-butanol did not use any mathematical modeling techniques. In this study, the asymmetric bioreduction of 1 was carried out in this work employing Lactobacillus paracasei BD71 biocatalyst and a novel hybrid design-based optimization approach. By using the hybrid design technique, the optimal circumstances were discovered to be pH = 7, temperature = 29 °C, incubation period = 66 h, and agitation speed = 189 rpm. Also, the enantiomeric excess (ee) and conversion could be 99.15 % and 98.19 %, respectively. Next, (S)-2 was acquired to be ee: 99 %, conversion: >99 %, and yield: 97 % from the optimum bioreduction conditions. Furthermore, 14.08 g of 1 under optimal conditions was entirely transformed into (S)-2 (13.84 g, 97 % isolated yield). This study is the first research attempt to use a biocatalyst and an innovative and new hybrid design-based optimization approach to fabricate enantiopure (S)-2 at a high gram scale. This work has successfully demonstrated that the new hybrid design-based optimization technique is applicable to biocatalytic asymmetric reduction processes.
AtıfScopus9WoS8OpenAlex5İncele - MakaleAçık Erişim2024Scopus SJRQ1A Multi-response Nonlinear Programming Model with an Inscribed Design to Optimize Bioreduction Conditions of (S)-phenyl (pyridin-2-yl)methanol by Leuconostoc pseudomesenteroides N13
Özdemir, Akın; Şahin, Engin
Asymmetric bioreductions have the potential to synthesize chiral alcohols when catalyzed by biocatalysts. Nevertheless, the (S)-phenyl (pyridin-2-yl)methanol ((S)-2) analgesic synthesis poses significant challenges concerning unsatisfactory substrate amount and production method. Thus, this study proposes an inscribed design-focused multi-response nonlinear optimization model for the asymmetric reduction of the phenyl(pyridin-2-yl)methanone (1) with Leuconostoc pseudomesenteroides N13 biocatalyst. From the novel inscribed design-focused multi-response nonlinear optimization model, optimization conditions of the reaction, such as pH = 6, temperature = 29 °C, incubation time = 53 h, and agitation speed = 153 rpm, were found. Also, the reaction conversion was predicted to be 99%, and the product of the enantiomeric excess (ee) was 98.4% under the obtained optimization conditions. (S)-2 was obtained with 99% ee, 99% conversion, and 98% yield while performing a validation experiment using the determined optimized conditions. In addition, 1 with the amount of 11.9 g was converted entirely to (S)-2 (11.79 g, 98% isolated yield) on a high gram scale. Also, this study is noted as the first example of the gram-scale production of (S)-2 using an optimization strategy and biocatalyst. Further, the applicability of the inscribed design-focused optimization model in biocatalytic reactions has been demonstrated and provides an effective process for the analgesic synthesis of (S)-2, which is a green, cost-effective method of producing chiral aryl heteroaryl methanol.
AtıfScopus3WoS3OpenAlex3İncele - MakaleAçık Erişim2024Scopus SJRQ2Green synthesis of (S)-1-(furan-2-yl)propan-1-ol from asymmetric bioreduction of 1-(furan-2-yl)propan-1-one using whole-cell of Lactobacillus paracasei BD101
Bülbül, Ali Savaş; Şahin, Engin
Chiral heterocyclic alcohols are important precursors for production of pharmaceutical medicines and natural products. (S)-1-(furan-2-yl)propan-1-ol ((S)-2) can be used production of pyranone, which can be used in the synthesis of sugar analogues, antibiotics, tirantamycines, and anticancer drugs. The synthetic approaches for (S)-2, however, have substantial difficulties in terms of inadequate enantiomeric excess (ee) and gram scale synthesis. Moreover, the biocatalytic synthesis of (S)-2 is unknown until now. In this study, the synthesis of (S)-2 was carried out by performing the asymmetric bioreduction of 1-(furan-2-yl)propan-1-one (1) using the Lactobacillus paracasei BD101 biocatalyst obtained from boza, a grain-based fermented beverage. (S)-2 was obtained with >99% conversion, >99% ee, and 96% yield under the optimized conditions. Furthermore, in 50 h, 8.37 g of 1 was entirely transformed into (S)-2 on gram scale (96% isolated yield, 8.11 g). This is the first report on the high-gram scale biocatalyzed synthesis of enantiopure (S)-2. These data suggest that L. paracasei BD101 can be used to bioreduction of 1 in gram scale and efficiently produce (S)-2. Furthermore, these findings laid the base for future study into the biocatalytic production of (S)-2. It was particularly notable as it was the highest known to date optical purity of (S)-2 generated by asymmetric reduction using a biocatalyst. This work offers a productive environmentally friendly method for producing (S)-2 using biocatalysts.
AtıfScopus10WoS10OpenAlex12İncele - MakaleYalnız künye2024Scopus SJRQ1Effective biocatalytic synthesis of enentiopure (R)-1,2-diphenylethanol as a pharmaceutical precursor using whole-cell biocatalyst
Çakmak, Fadile; Özdemir, Akın; Dertli, Enes; Şahin, Engin
Optically active alcohols are crucial precursors. 1,2-Diarylethanols and their analogues constitute a significant group of substances of biological significance. The biocatalytic synthesis of (R)-1,2-diphenylethanol ((R)-2), which can be utilized as a precursor to important drugs, is still not at the desired level in terms of substrate amount and production process. This study asymmetrically reduced 1,2-diphenylethanone (1) using the Lactobacillus paracasei BD87E6 biocatalyst and a novel orthogonal quadratic design-embedded optimization approach. The following reaction optimization conditions were determined using the suggested optimization technique: pH = 6, temperature = 31 °C, incubation period = 48 h, and agitation speed=134 rpm. In addition, the reaction conversion was estimated to be 99.38 %, and the product's enantiomeric excess (ee) was estimated to be 99.12 %. Further, (R)-2 was produced with >99 % ee, >99 % conversion, and 98 % yield in the experimental investigation under the established optimum conditions. This study is the first attempt to reduce substrate 1 to (R) or (S)-2 using a mathematical optimization method in the presence of a biocatalyst. Furthermore, on a high-gram scale, 1 (15.70 g) was entirely transformed into (R)-2 (15.54 g, 98 % isolated yield). Notably, this study is also the first to perform the gram-scale production of (R)-2 using a novel optimization approach and a biocatalyst. Finally, the innovative and novel orthogonal quadratic design-embedded optimization technique has been demonstrated as an efficient, cost-effective, and environmentally friendly biocatalytic procedure for synthesizing (R)-2.
AtıfScopus7WoS7OpenAlex6İncele - MakaleYalnız künye2023Scopus SJRQ2Design, synthesis, antioxidant and anticholinesterase activities of novel isonicotinic hydrazide-hydrazone derivatives
Aslanhan, Özlem; Kalay, Erbay; Tokalı, Feyzi Sinan; Can, Zehra; Şahin, Engin
The design and synthesis of hydrazone derivatives are increasing in popularity day by day due to the significant biological activities of this scaffold. In the present study, twelve novel isonicotinic hydrazide-hydrazone analogues were synthesized by the condensation reaction of isonicotinic hydrazide with benzaldehyde possessing sulfonate moiety. The structures of the novel compounds have been characterized in detail using spectroscopic techniques. All compounds have shown inhibitory effects against the AChE enzyme at rates ranging from 21.00 to 59.48%. Among them, compound 5 has exhibited the best inhibitory effect of 59.48% against AChE at a concentration of 0.1 mM. Furthermore, to determine how effective the novel compounds are as antioxidants, FRAP and DPPH studies were also carried out. FRAP values in compounds 1–12 were found to range from 26.989–3415.556 µmol FeSO4.7H2O/mg. They also displayed moderate antioxidant potential in the range of SC50=0.03–87.32 mg/mL compared with the control Trolox (SC50 =0.004) in DPPH radical scavenging activities. It was seen that the AChE inhibition percentages of the compounds were in the range of 23.04–58.10% at 0.1 mM concentration. This is the first research on the synthesis, antioxidant and enzyme inhibition properties of these compounds.
AtıfScopus43WoS37OpenAlex44İncele - MakaleYalnız künye2023Scopus SJRQ2Efficient bioreduction of 1-(furan-2-yl)ethanone into enantiomerically pure drug precursor by Lactobacillus paracasei BD101
Şahin, Engin
Asymmetric bioreduction catalyzed by biocatalyst have shown considerable potential in the preparation of chiral alcohols. (R)-1-(furan-2-yl)ethanol ((R)-2) can be used precursor in the synthesis of many naturally bioactive piperidine alkaloids such as (−)-Cassine, (−)-Spectaline, (−)-Carnavaline, Prosafrine and (−)- Prosafrinine. Moreover, (R)-2 a key chiral precursor in the production of α, β-unsaturated δ- lactones, which have antifungal, antibiotic, and cytotoxic effects on human tumor cells. However, the synthesis routes of (R)-2 still pose significant challenges in term of unsatisfactory enantiomeric excess (ee) and gram scale synthesis. In this study, Lactobacillus paracasei BD101 biocatalyst from boza, a cereal-based fermented beverage, for the asymmetric bioreduction of the 1-(furan-2-yl)ethanone (1). Following biocatalytic process optimization, (R)-2 was generated with >99% ee and 97% yield. In addition, 9.9 g of 1 was completely converted into (R)-2 on a gram scale (9.78 g, 97% isolated yield) in 48 h. This is the first report about the fabrication of enantiopure (R)-2 in high gram scale using biocatalyst. The optical purity of (R)-2 produced by asymmetric reduction with L paracasei BD101 was also noteworthy since it was the highest documented to date. This study provides an efficient green process for the biocatalytic synthesis of (R)-2.
AtıfScopus16WoS15OpenAlex14İncele - MakaleAçık Erişim2023Scopus SJRQ3Synthesis of Arylsulfonyl Hydrazone Derivatives: Antioxidant Activity, Acetylcholinesterase Inhibition Properties, and Molecular Docking Study
Demirci, Yasin; Kalay, Erbay; Kara, Yakup; Güler, Halil İbrahim; Can, Zehra; Şahin, Engin
In this current paper, fifteen novel sulfonyl hydrazone derivatives have been successfully synthesized and evaluated for antioxidant activity as well as their effects on inhibitory activity toward acetylcholinesterase (AChE). By using 1H NMR, 13C NMR, FT-IR, and high-resolution mass spectrometry methods, the full characterization data of the novel compounds were obtained. The synthesized compounds capacity to inhibition glucosidase and exhibit antioxidant activity were tested in vitro. It was determined that compounds (E)-4-((2-((4-chlorophenyl)sulfonyl)hydrazone)methyl)-2-methoxyphenylfuran-2-carboxylate (21), (E)-2-methoxy-4-((2-(phenylsulfonyl)hydrazone)methyl)phenylfuran-2-carboxylate (17) and (E)-4-((2-((4-bromophenyl)sulfonyl)hydrazone)methyl)-2-methoxyphenylfuran-2-carboxylate (25) showed good antioxidant activity. Upon examining the acetylcholinesterase inhibitory activity, it was determined that compounds (E)-2-methoxy-4-((2-((4-methoxyphenyl)sulfonyl) hydrazone)methyl)phenylacetate (27) (10.39 μM), (E)-4-((2-((4-chloro phenyl)sulfonyl) hydrazone)methyl)-2-methoxyphenylfuran-2-carboxylate (21) (10.81 μM), (E)-4-((2-((4-chloro phenyl)sulfonyl)hydrazone)methyl)-2-methoxyphenyl thiophene-2-carboxylate (22) (12.92 μM) and (E)-2-methoxy-4-((2-(phenylsulfonyl)hydrazone)methyl)phenylfuran-2-carboxylate (17) (12.93 μM) showed potent inhibitory effects. Molecular docking simulations were used to investigate the interactions of novel sulfonyl hydrazone derivatives with human acetylcholinesterase protein. The ligands exhibited strong binding to the receptor protein with potent inhibition.
AtıfScopus18WoS18OpenAlex19İncele - MakaleYalnız künye2023Scopus SJRQ3Modified distance optimization method for the asymmetric bioreduction conditions of phenyl(thiophen-2-yl)methanone by Weissella paramesenteroides N7
Özdemir, Akın; Şahin, Engin
Chirality plays a significant part in life since it is closely linked to carrying out the many metabolic processes that make up a living being. Chiral secondary alcohols such as diaryl-, aryl heteroaryl-, and diheteroaryl are employed in pharmaceuticals as drug intermediates. Although biocatalytic asymmetric reduction of prochiral ketones containing aromatic and heteroaromatic groups is widely known, biocatalytic reduction of heteroaromatic prochiral ketones containing sulfur heteroatoms is rarely known. Very few studies exist in the literature, including the biocatalytic reduction of phenyl(thiophen-2-yl)methanone (1). Moreover, the biocatalytic reduction of 1 with a mathematical modelling and optimization technique is unknown until now. In this study, Weissella paramesenteroides N7 biocatalyst for the asymmetric bioreduction of 1 using a novel modified distance optimization method. Optimization conditions were found as pH = 6.46, temperature = 26 °C, incubation period = 71 h, agitation speed = 200 rpm by the modified distance optimization method, and it was determined that the conversion and enantiomeric excess (ee) under these conditions could be 98.7% and 98%, respectively. Under these proposed optimization conditions, (S)-phenyl(thiophen-2-yl)methanol ((S)-2) was obtained with >99% ee, >99% conversion, and 97% yield. In addition, 11.29 g of 1 was completely converted into (S)-2 (11.07 g, 97% isolated yield) under optimized conditions. This is the first report about the fabrication of enantiopure (S)-2 in high gram scale using a biocatalyst and a novel modified distance optimization technique. In this study, the successful applicability of the new modified distance optimization method in biocatalytic asymmetric reduction reactions has been successfully demonstrated.
AtıfScopus3WoS3OpenAlex5İncele - MakaleAçık Erişim2023Scopus SJRQ2Efficient bio-catalytic production of enentiopure (S)-(4-chlorophenyl)(phenyl)methanol as a drug precursor by using a novel rotatable composite design-based optimization strategy
Tozlu, Nesrullah; Bülbül, Ali Savaş; Özdemir, Akın; Şahin, Engin
Asymmetric bioreductions catalyzed by biocatalysts have demonstrated great promise in manufacturing chiral alcohols. On the other hand, the synthesis of (S)-(4-chlorophenyl)(phenyl)methanol ((S)-2), precursors of L-cloprastine and carbinoxamine, still presents considerable challenges due to the inadequate substrate quantity and production process. In this work, a novel rotatable composite design-based optimization technique was used with the Lactobacillus paracasei BD101 biocatalyst for the asymmetric reduction of (4-chlorophenyl)(phenyl)methanone (1). Optimization conditions of the reaction were determined by the proposed optimization strategy as: pH=5.85, temperature=37 °C, incubation time=71 h, and agitation speed=120 rpm. The reaction conversion and the product of enantiomeric excess (ee) were also predicted to be 97% and 99%, respectively. In the experimental study performed under the determined optimized conditions, (S)-2 was obtained with >99% ee, >99% conversion, and 97% yield. In addition, 1 with the amount of 15.166 g was completely converted to (S)-2 (14.85 g, 97% isolated yield) on a high-gram scale. Notice that the manufacture of (S)-2 on a gram scale utilizing a biocatalyst and an optimization technique is demonstrated in this work for the first time. Finally, an economical, effective, and environmentally friendly biocatalytic process for the biocatalytic synthesis of (S)-2, which have antitussive and antiemetic properties and relax the bronchial muscle, has been demonstrated by the novel rotatable composite design-based optimization method.
AtıfScopus3WoS3OpenAlex2İncele - MakaleAçık Erişim2023Scopus SJRQ3Optimization of asymmetric bioreduction conditions of 1-(thiophen-2-yl)ethanone by Weissella cibaria N9 using a desirability function-embedded face-centered optimization model
Bolubaid, Mohammed; Özdemir, Akın; Dertli, Enes; Alamoudi, Mohammed; Taylan, Osman; Karaboğa, Derviş; Yılmaz, Mustafa Tahsin; Şahin, Engin
Prochiral ketones can be effectively bio-reduced to chiral secondary alcohols by whole-cell biocatalysts, which are possible useful precursors to synthesize physiologically active chemicals and natural products. When whole-cell biocatalysts strains are used, bioreduction process can be influenced by various cultural factors, and it is vital to optimize these factors that affect selectivity, conversion rate, and yield. In this study, Weissella cibaria N9 was used as whole-cell biocatalyst for bioreduction of 1-(thiophen-2-yl)ethanone, and cultural design factors were optimized using a desirability function-embedded face-centered optimization model. For this, effects of pH (4.5–5.5–6.5, x 1), (2) temperature (25–30–35 °C, x 2), (3) incubation period (24–48–72 h, x 3), and (4) agitation speed (100–150–200 rpm, x 4) on two response variables; (1) ee (%) and (2) cr (%) were tested. Next, desirability function-embedded face-centered optimization model revealed that a pH of 6.43, a temperature of 26.04 °C, an incubation period of 52.41 h, and an agitation speed of 150 rpm were the optimum levels and the estimated ee and cr responses were 99.31% and 98.16%, respectively. Importantly, the actual experimental ee and cr responses were similar to the estimated values indicating the capability of the offered desirability function-embedded face-centered optimization model when using the optimum cultural conditions.
AtıfScopus1WoS1OpenAlex3İncele - MakaleAçık Erişim2022Scopus SJRQ2Efficient bioreduction of cyclohexyl phenyl ketone by Leuconostoc pseudomesenteroides N13 biocatalyst using a distance-based design-focused optimization model
Özdemir, Akın; Şahin, Engin
Whole-cell biocatalysts have been a popular method for the preparation of chiral alcohols. Although asymmetric reduction of cyclohexyl(phenyl)methanone (1) by chemical catalysts is common, a biocatalytic asymmetric reduction is extremely rare. In this respect, we report herein that Leuconostoc pseudomesenteroides N13 was successfully employed as a biocatalyst to reduce 1 to (S)-cyclohexyl(phenyl)methanol ((S)-2). Furthermore, the use of a mathematical optimization strategy for asymmetric reduction of substrate 1 is not known in the current literature. The new distance-based design-focused optimization model was used to enhance the conversion of the substrate, enantiomeric excess (ee) of product, and yield. The distance-based design-focused optimization model identified the following optimal bioreduction conditions: pH=6.46, temperature=30°C, incubation period=72 hours, and agitation speed=199 rpm. Then it was stated that under these ideal conditions, (S)-2 may be produced with 99 % ee and 98.46 % conversion rate (cr). (S)-2 was achieved with 99% ee, and 99% cr as a consequence of the experimental reaction carried out under the indicated optimization conditions. It has been shown that Leuconostoc pseudomesenteroides N13 can be utilized as a biocatalyst in asymmetric reduction reactions. This study, in addition to being the first example of a bioreduction of substrate 1 by mathematical optimization, also demonstrates for the first time the distance-based design-focused model can be used in the bioreduction reaction.
AtıfScopus9WoS9OpenAlex8İncele - MakaleAçık Erişim2022Scopus SJRQ1Optimization of Asymmetric Bioreduction Conditions of 2-methyl-1-phenylpropan-1-one by Lactobacillus fermentum BY35 Using I-Optimal Design-Based Model
Aksuoğlu, Selmani; Özdemir, Akın; Serencam, Hüseyin; Dertli, Enes; Şahin, Engin
The bioreduction of prochiral ketones offers efficient access to chiral secondary alcohols, which are potentially beneficial precursors for producing many biologically active compounds and natural products. This bioreduction process can be affected by different parameters when whole-cell of biocatalysts such as Lactic Acid Bacteria strains are applied. In this context, this paper proposed an I-optimal design-based model to optimize culture parameters such as temperature, pH, incubation period, and agitation speed for asymmetric bioreduction of 2-methyl-1-phenylpropan-1-one (1) with Lactobacillus fermentum BY35 as a biocatalyst while achieving the highest conversion rate (cr) and enantiomeric excess (ee). The optimum settings of the four culture parameters and the cr and ee values were found using the proposed optimization model as follows: pH = 6.5, temperature = 25 °C, incubation period = 38.5 h, agitation speed = 200 rpm, the ee value = 98.78%, and the cr value = 98.92%. After the validation of the process, the cr and ee values were found to be > 99% and > 99%, respectively, while using the optimum operating conditions from the optimization model. Thus, the results of the optimization model are consistent with the results of the validation experiment. It is also noted that this paper is the first to optimize culture parameters using the proposed I-optimal design-based model for an asymmetric reduction.
AtıfScopus3WoS3OpenAlex3İncele - MakaleYalnız künye2022Scopus SJRQ3Optimization of asymmetric reduction conditions of 2-bromo-1-(naphthalen-2-yl)ethanone by Enterococcus faecium BY48 biocatalyst with A-optimal design-embedded model
Özdemir, Akın; Şahin, Engin
Aromatic α-halohydrins, especially 2-haloethanols, which are a common pharmacological precursor, may be readily transformed to chiral β-adrenergic receptor blockers. Studies including the synthesis of (S)-2-bromo-1-(naphthalen-2-yl)ethanol ((S)-2), an α-halohydrin, in high conversion, enantiomeric excess (ee), and yield by biocatalytic asymmetric reduction of 2-bromo-1-(naphthalen-2-yl)ethanone (1) are still insufficient. Moreover, asymmetric reduction of substrate 1 using a mathematical optimization method is not explored in the current literature. In this article, the four asymmetric bioreduction conditions, which are (1) pH, (2) temperature, (3) incubation period, and (4) agitation speed, of substrate 1 were optimized to obtain (S)-2 with A-optimal design-embedded model in the presence of Enterococcus faecium BY48. Optimum bioreduction conditions were determined by the A-optimal design-embedded model as follows: pH = 7, temperature = 25°C, incubation period = 24 h, and agitation speed = 200 rpm. And then, it was suggested that (S)-2 could be obtained with 98.88% ee and 100% conversion rate (cr) under these optimum conditions. As a result of the experimental reaction performed under the optimization conditions suggested by the model, (S)-2 was obtained with 99% ee and 100% cr. The study revealed that E. faecium BY48 could be used as a biocatalyst in asymmetric reduction reactions. Also, the A-optimal design-embedded model could have the great potential to obtain the optimum asymmetric bioreduction conditions.
AtıfScopus3WoS3OpenAlex4İncele - MakaleAçık Erişim2022Scopus SJRQ1Optimization of Biocatalytic Production of Enantiopure (S)-1-(4-Methoxyphenyl) Ethanol with Lactobacillus senmaizuke Using the Box–Behnken Design-Based Model
Kavi, Mervenur; Özdemir, Akın; Dertli, Enes; Şahin, Engin
Enantiomerically pure (S)-1-(4-methoxyphenyl) ethanol is a significant molecule for the production of various drug intermediates. (S)-1-(4-methoxyphenyl) ethanol was synthesized from 4-methoxyacetophenone using Lactobacillus senmaizuke as a biocatalyst. In addition, optimization of experimental conditions is important to analyze the role of culture parameters for catalytic bioreduction reactions. For this particular purpose, the experimental conditions of pH, incubation period, temperature, and agitation speed were investigated with the Box–Behnken experimental design-based proposed optimization model. (S)-1-(4-methoxyphenyl) ethanol, which can be used for the synthesis of antihistamines, including diphenhydramine hydrochloride and loratadine cycloalkyl [b] indoles that have the treatment function for an allergic response, was obtained in > 99% conversion, > 99% enantiomeric excess and 96% yield with whole cells of L. senmaizukei at this optimization conditions: pH = 5.80, the temperature = 29 °C, incubation period = 50 h, and agitation speed = 155 rpm. The bioreduction of 4-methoxyacetophenone efficiency was importantly affected by the quadratic and linear effects of experimental design parameters. Besides, the results demonstrate the importance of design parameters for catalytic bioreduction reactions. It is also concluded that the results show the effectiveness of the Box–Behnken experimental design-based proposed model to obtain optimum operating conditions of design parameters for catalytic bioreduction reactions.
AtıfScopus4WoS4OpenAlex4İncele - MakaleYalnız künye2022Scopus SJRQ2Synthesis of 7-azaindole based carbohydrazides and 1,3,4-oxadiazoles; Antioxidant activity, α-glucosidase inhibition properties and docking study
Izgi, Samet; Sengul, Ibrahim F.; Şahin, Engin; Koca, Mehmet Serdar; Cebeci, Fatma; Kandemir, Hakan
In this current work, 7-azaindole based 1,3,4-oxadiazoles have been successfully prepared by treatment of 3-(hydrazonomethyl)-7-azaindole with the different acyl chlorides or acetic anhydrides to give the corresponding carbohydrazides, followed by iodine mediated synthetic protocol in order to afford the corresponding 2,5-disubstituted 1,3,4-oxadiazoles. The full characterization data of the novel compounds were obtained by utilizing 1H NMR, 13C NMR, FT-IR, high-resolution mass spectrometry and single crystal X-ray diffraction techniques. The antioxidant activity and α-glucosidase inhibition potential of the prepared compounds are examined by in vitro assays. The targeted hydrazide linked 7-azaindoles and their corresponding cyclized form 1,3,4-oxadiazoles exhibited inhibitory potential with IC50 values ranges between 0.46 and 24.92 mM. Plausible binding mode and interaction of ligands with α-glucosidase enzyme have been studied by molecular docking, supporting the experimental results.
AtıfScopus28WoS27İncele - MakaleAçık Erişim2022Scopus SJRQ3Production of enantiomerically enriched chiral carbinols using whole-cell biocatalyst
Baydaş, Yasemin; Kalay, Erbay; Şahin, Engin
Biocatalytic asymmetric reduction of ketone is an efficient method for the production of chiral carbinols. The study indicates selective bioreduction of different ketones (1–8) to their respective (R)-alcohols (1a–8a) in low to high selectivity (0- >99%) with good yields (11–96%). In this work, whole-cell of Lactobacillus kefiri P2 catalysed enantioselective reduction of various prochiral ketones was investigated. (R)-4-Phenyl-2-butanol 2a, which is used as a precursor to antihypertensive agents and spasmolytics (anti-epileptic agents), was obtained using L kefiri P2 in 99% conversion and 91% enantiomeric excess (ee). Moreover, bioreduction of 2-methyl-1-phenylpropan-1-one substrate 8, containing a branched alkyl chain and difficult to asymmetric reduction with chemical catalysts as an enantioselective, to (R)-2-methyl-1-phenylpropan-1-ol (8a) in enantiomerically pure form was carried out in excellent yield (96%). The gram-scale production was carried out, and 9.70 g of (R)-2-methyl-1-phenylpropan-1-ol (8a) in enantiomerically pure form was obtained in 96% yield. Also especially, the yield and gram scale of (R)-2-methyl-1-phenylpropan-1-ol (8a) synthesised through catalytic asymmetric reduction using the biocatalyst was the highest report so far. The efficiency of L kefiri P2 for the conversion of the substrates and ee of products were markedly influenced by the steric factors of the substrates. This is a cheap, clean and eco-friendly process for production of chiral carbinols compared to chemical processes.
AtıfScopus5WoS5OpenAlex6İncele - MakaleYalnız künye2022Scopus SJRQ3Gram-scale synthesis of (S)-1-(thiophen-2-yl)ethanol in high enantiomeric purity under Enterococcus faecium BY48 biocatalysts
Şahin, Engin
Sulfur-containing chiral heterocyclic secondary alcohols are relevant intermediates in the preparation of enantiomerically pure compounds endowed with biological activity. In this report, we evaluated the reductive potential of different lactic acid bacteria as whole-cell biocatalysts of the enantioselective reduction of 1-(thiophen-2-yl)ethanone (1). Enterococcus faecium BY48, isolated from boza, a cereal-based fermented beverage, was found to be the best biocatalyst in our initial investigations. Using whole-cell preparations of E. faecium BY48, we then systematically analyzed the reaction parameters (pH, incubation period, agitation speed, and temperature) to optimize the yield, the enantiomeric excess (e. e.), and the conversion leading to (S)-1-(thiophen-2-yl)ethanol [(S)-2]. The target derivative, which is a precursor in the synthesis of biologically active chiral compounds, was obtained in enantiomerically pure form, gram-scale amounts, and high yield. This is also the first report that the manufacture of (S)-2 in excellent conversion, yield, enantiopure form, and gram scale used whole-cell biocatalyst. This whole-cell E. faecium BY48 biocatalyzed reaction is a clean, environmentally friendly, and cost-effective process, representing a valuable alternative to chemical catalysis or previously reported biocatalytic procedures in the preparation of (S)-2.
AtıfScopus3WoS3OpenAlex5İncele