A review: FDA-approved fluorine-containing small molecules from 2015 to 2022.

Fluorine-containing small molecules have occupied a special position in drug discovery research. The successful clinical use of fluorinated corticosteroids in the 1950s and fluoroquinolones in the 1980s led to an ever-increasing number of approved fluorinated compounds over the last 50 years. They have shown various biological properties such as antitumor, antimicrobial, and anti-inflammatory activities. Fluoro-pharmaceuticals have been considered a strong and practical tool in the rational drug design approach due to their benefits from potency and ADME (absorption, distribution, metabolism, and excretion) points of view. Herein, approved fluorinated drugs from 2015 to 2022 were reviewed.

Synthesis and structure-activity relationship studies of benzimidazole-thioquinoline derivatives as α-glucosidase inhibitors.

In this article, different s-substituted benzimidazole-thioquinoline derivatives were designed, synthesized, and evaluated for their possible α-glucosidase inhibitory activities. The most active compound in this series, 6j (X = 4-bromobenzyl) exhibited significant potency with an IC50 value of 28.0 ± 0.6 µM compared to acarbose as the positive control with an IC50 value of 750.0 µM. The kinetic study showed a competitive inhibition pattern against α-glucosidase for the 6j derivative. Also, the molecular dynamic simulations were performed to determine key interactions between compounds and the targeted enzyme. The in silico pharmacodynamics and ADMET properties were executed to illustrate the druggability of the novel derivatives. In general, it can be concluded that these derivatives can serve as promising leads to the design of potential α-glucosidase inhibitors.

Design, synthesis, spectroscopic characterization, in vitro tyrosinase inhibition, antioxidant evaluation, in silico and kinetic studies of substituted indole-carbohydrazides.

In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including 1H NMR, 13C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC50 values in the range of 0.070 to > 100 µM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC50 = 0.070 µM), 8f (R = 4-OH, IC50 = 0.072 µM), and 19e (IC50 = 0.19 µM) with para-OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 µM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281.

Fe3O4@SiO2@CeO2 as a Potential Nanomagnetic Carrier for Oral Delivery System and Release of Celecoxib.

AIMS AND OBJECTIVE: In this study, an attempt was made to synthesize, characterize, and develop many applications of functionalized rare metal oxide nanoparticles. Herein, a new strategy for drug delivery is developed to functionalize magnetite nanoparticles to improve their performances in the delivery of celecoxib. MATERIALS AND METHODS: Magnetite Fe3O4@SiO2 nanoparticles are synthesized by the sol-gel method. The surface of the hydroxyl groups was extended by treating with cerium nitrate salt; finally, sodium hydroxide was anchored to the surface hydroxyl groups to produce cerium oxidefunctionalized Fe3O4@SiO2@CeO2 magnetic nanoparticles (FSC). The synthesized sample was characterized by FT-IR, FESEM, VSM, TGA, and XRD. Afterward, the functionalized nanoparticles were examined in the delivery of celecoxib as an active drug model involving cerium oxide and hydroxyl functional groups. RESULTS: For this purpose, the amount of loading/release of the drug was investigated in different amounts of nanocomposite and pH values. CONCLUSION: The results of the present investigation indicate that the formulations (mFSC=5 mg, pH=3.3) can be considered as best among various formulations with respect to particle size, entrapment efficiency, and in-vitro successful drug release.

Synergistic Cytotoxic and Apoptotic Effects of Local Probiotic Lactobacillus Brevis Isolated from Regional Dairy Products in Combination with Tamoxifen.

Tamoxifen (TAM), the most widely used anti-estrogenic drug, inhibits the progression of breast cancer through competing with estrogen for binding to the estrogen receptor (ER). Tamoxifen has been the first-line adjuvant endocrine therapy in pre- and postmenopausal patients with ER + breast cancer for two decades. However, due to its side effects, interest in using anticancer agents derived from natural foods has increased. It has recently been stated that some probiotics can improve the efficacy of anticancer drugs via synergistic effects. Here, Local Probiotic Lactobacillus Brevis were isolated and characterized from dairy products and its supernatant was prepared. Proliferation of MCF-7, a breast cancer cell line, was investigated after treatment with Lactobacillus Brevis supernatant (LBS) solely, and in combination with Tamoxifen. In Vitro trials were performed to assess the LBS potency. Bax and Bcl-2 mRNA expression levels and apoptotic effects after these treatments were examined by qRT-PCR and flow cytometry, respectively. The results indicated that LBS induces apoptosis in MCF-7 at high concentrations. Transcription of Bcl-2 was reduced but Bax mRNA expression was enhanced. Tamoxifen's inhibitory effect on the cell growth was synergistically augmented by LBS. In addition, we found that the Bcl-2 mRNA levels in the cells exposed to TAM/LBS were lower than in those treated with TAM alone. Our findings suggest potential role of LB as an adjuvant therapy in cancer treatment and prevention; along with its underlying mechanism.

Synthesis of 4-alkylaminoimidazo[1,2-a]pyridines linked to carbamate moiety as potent α-glucosidase inhibitors.

In this work, various imidazo[1,2-a]pyridines linked to carbamate moiety were designed, synthesized, and evaluated for their α-glucosidase inhibitory activity. Among synthesized compounds, 4-(3-(tert-Butylamino)imidazo[1,2-a]pyridin-2-yl)phenyl p-tolylcarbamate (6d) was the most potent compound (IC50 = 75.6 µM) compared with acarbose as the reference drug (IC50 = 750.0 µM). Kinetic study of compound 6d indicated a competitive inhibition. Also, the molecular docking study suggested desired interactions with the active site residues. In particular, hydrogen bonds and electrostatic interactions constructed by compound 6d afforded well-oriented conformation in the 3A4A active site.

Design and Synthesis of Novel Arylisoxazole-Chromenone Carboxamides: Investigation of Biological Activities Associated with Alzheimer's Disease.

A novel series of hybrid arylisoxazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase (ChE) inhibitory activity based on the modified Ellman's method. Among synthesized compounds, 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide depicted the most acetylcholinesterase (AChE) inhibitory activity (IC50 =1.23 µm) and 5-(3-chlorophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide was found to be the most potent butyrylcholinesterase (BChE) inhibitor (IC50 =9.71 µm). 5-(3-Nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide was further investigated for its BACE1 inhibitory activity as well as neuroprotectivity and metal chelating ability as important factors involved in onset and progress of Alzheimer's disease. It could inhibit BACE1 by 48.46 % at 50 µm. It also showed 6.4 % protection at 25 µm and satisfactory chelating ability toward Zn2+ , Fe2+ , and Cu2+ ions. Docking studies of 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide and 5-(3-chlorophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide confirmed desired interactions with those amino acid residues of the AChE and BChE, respectively.

Synthesis and Biological Activity of Some Benzochromenoquinolinones: Tacrine Analogs as Potent Anti-Alzheimer's Agents.

Alzheimer's disease (AD) is a well-known neurodegenerative disorder affecting millions of old people worldwide and the corresponding epidemiological data emphasize the importance of the disease. As AD is a multifactorial illness, various single target directed drugs that have reached clinical trials have failed. Therefore, various factors associated with outset of AD have been considered in targeted drug discovery. In this work, various benzochromenoquinolinones were synthesized and evaluated for their cholinesterase and BACE1 inhibitory activities as well as neuroprotective and metal-chelating properties. Among the synthesized compounds, 14-amino-13-(3-nitrophenyl)-2,3,4,13-tetrahydro-1H-benzo[6,7]chromeno[2,3-b]quinoline-7,12-dione (6m) depicted the best inhibitory activity toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 s of 0.86 and 6.03 µm, respectively. Also, the compound could inhibit ß-secretase 1 (BACE1) with IC50 =19.60 µm and showed metal chelating ability toward Cu2+ , Fe2+ , and Zn2+ . In addition, docking study demonstrated desirable interactions of compound 6m with amino acid residues characterizing AChE, BChE, and BACE1.

Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole-Phenylpiperazine Derivatives.

In this work, a novel series of arylisoxazole-phenylpiperazines were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that [5-(2-chlorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5c) was the most potent AChE inhibitor with IC50 of 21.85 µm. It should be noted that most of synthesized compounds showed no BChE inhibitory activity and [5-(2-fluorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5a) was the most active anti-BChE derivative (IC50 =51.66 µm). Also, kinetic studies for the AChE and BChE inhibitory activity of compounds 5c and 5a confirmed that they have simultaneously bound to the catalytic site (CS) and peripheral anionic site (PAS) of both AChE and BChE. Furthermore, docking study of compound 5c showed desired interactions of that compound with amino acid residues located in the active and peripheral anionic sites. Compound 5c was also evaluated for its BACE1 inhibitory activity and demonstrated IC50 =76.78 µm. Finally, neuroprotectivity of compound 5c on Aß-treated neurotoxicity in PC12 cells depicted low activity.

Design, synthesis and anti-Alzheimer's activity of novel 1,2,3-triazole-chromenone carboxamide derivatives.

Alzheimer's disease (AD) is a well-known neurodegenerative disorder affecting millions of old people worldwide and the corresponding epidemiological data highlights the significance of the disease. As AD is a multifactorial illness, various single-target directed drugs that have reached clinical trials have failed. Therefore, various factors associated with outset of AD have been considered in targeted drug discovery and development. In this work, a wide range of 1,2,3-triazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase inhibitory activity. Among them, N-(1-benzylpiperidin-4-yl)-7-((1-(3,4-dimethylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-oxo-2H-chromene-3-carboxamide (11b) showed the best acetylcholinesterase inhibitory activity (IC50 = 1.80 µM), however, it was inactive toward butyrylcholinesterase. It should be noted that compound 11b was evaluated for its BACE1 inhibitory activity and calculated IC50 = 21.13 µM confirmed desired inhibitory activity. Also, this compound revealed satisfactory neuroprotective effect against H2O2-induced cell death in PC12 neurons at 50 µM as well as metal chelating ability toward Fe2+, Cu2+, and Zn2+ ions.

Novel quinazolin-4(3H)-one linked to 1,2,3-triazoles: Synthesis and anticancer activity.

In this work, a wide range of novel quinazolin-4(3H)-one linked to 1,2,3-triazoles was designed, synthesized, and evaluated against a panel of three human breast (MDA-MB-231, MCF-7, T-47D), lung (A549), and prostate (PC3) cancer cell lines. Our results revealed that the anticancer activity of the synthesized compounds was selectively affected by the presence of methoxy group on the linker between quinazolinone and 1,2,3-triazole moieties. According to the calculated IC50 values, compounds 6q, 6w, and 6x showed good cytotoxicity against breast cancer cell lines even more effective than the reference drug, etoposide. Compounds 6q and 6u were found to be potent compounds against A549, non-small-cell lung cancer (NSCLC), comparing with erlotinib. Also, the morphological analysis by acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that potent compounds induced apoptosis in human cancer cell lines. Molecular docking studies were performed to clarify the inhibition mode of compounds 6g, 6u, 6w, and 6x over the EGFR active site. The most promising compounds, 6q and 6u, possessing 3-methoxy group were well oriented to the gatekeeper hydrophobic pocket of EGFR active site and interact well with Ala719, Val702, and Leu820 through hydrophobic interaction.

N-substituted indole carbohydrazide derivatives: synthesis and evaluation of their antiplatelet aggregation activity.

BACKGROUND: Platelet aggregation is one of the most important factors in the development of thrombotic disorders which plays a central role in thrombosis (clot formation). Prophylaxis and treatment of arterial thrombosis are achieved using anti-platelet drugs. In this study, a series of novel substituted indole carbohydrazide was synthesized and evaluated for anti-platelet aggregation activity induced by adenosine diphosphate (ADP), arachidonic acid (AA) and collagen. METHODS: Our synthetic route started from methyl 1H-indole-3-carboxylate (1) and ethyl 1H-indole-2-carboxylate (4) which were reacted with hydrazine monohydrate 99%. The aldol condensation of the later compound with aromatic aldehydes led to the formation of the title compounds. Sixteen indole acylhydrazone derivatives, 3d-m and 6d-i were tested for anti-platelet aggregation activity induced by adenosine diphosphate (ADP), arachidonic acid (AA) and collagen. RESULTS: Among the synthesized compounds, 6g and 6h with 100% inhibition, proved to be the most potent derivatives of the 2-substituted indole on platelet aggregation induced by AA and collagen, respectively. In 3-substituted indole 3m with 100% inhibition and 3f and 3i caused 97% inhibition on platelet aggregation induced by collagen and AA, respectively. CONCLUSION: In this study, compounds 6g, 6h, 3m, 3f and 3i showed better inhibition on platelet aggregation induced by AA and collagen among the title compounds. Quantitative structure-activity relationship (QSAR) analysis between the structural parameters of the investigated derivatives and their antiplatelet aggregation activity was performed with various molecular descriptors but, analysis of the physicochemical parameters doesn't show a significant correlation between the observed activities and general molecular parameters of the synthesized derivatives. Although, due to the existence of several receptors on the platelets surface which are responsible for controlling the platelet aggregation, the investigated compounds in the present study may exert their activities through binding to more than one of these receptors and therefore no straight forward SAR could be obtained for them.