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In view of the extremely important biological and medicinal properties of napthofurans, the synthesis of these heterocycles has fascinated the interest of medicinal and organic chemists. Keeping this in mind, we herein report the synthesis and antimicrobial evaluation of 4-N-aryl-naphtho[2,1-b]furo[3,2-d] pyrimidines 5 (a–l). Structures of these synthesized compounds were confirmed by spectral analysis like IR, NMR, and Mass spectrometry. The in vitro antimicrobial activities were reported for all the compounds 5 (a–l). The compounds 5e and 5f exhibited excellent antibacterial, antifungal, and antidermatophytic activities against tested pathogens at MIC 3.125, and 3.125 µg/mL, respectively. Furthermore, molecular docking studies of these compounds against S. aureus tyrosyl-tRNA synthetase (PDB ID: 1JIJ), S. aureus Gyrase (PDB ID: 2XCT), and SARS-CoV-2 Omicron (PDB ID: 7TOB), revealed the potential binding mode of the ligands to the site of the appropriate targets. Finally, drug-likeness and structure-activity relationship studies were also disclosed. [ABSTRACT FROM AUTHOR]

Ferula species have occupied great value in traditional medicine in various countries. The aim of the present paper was to assess for the first time to the phytochemical profile of Ferula tunetana Pomel ex Batt. (F. tunetana) seed and leaf extracts using HPLC-MS/MS, as well as to evaluate their antioxidant and anti- α -amylase activities. Therefore, total phenolic and flavonoid amounts of the studied extracts were determined and 38 compounds were detected and quantified (phenolic acids, flavonoids, non-phenolic acid and stilbenes). In addition of their antioxidant potential against 1,1-diphenyl-2-picrylhydrazyl (DPPH) and Ferric Reducing Antioxidant Power (FRAP) assays, in vitro and in silico studies were adopted to evaluate α -amylase inhibitory properties of F. tunetana extracts. Ethyl acetate (EtOAc) seed extract showed the highest total phenolic content, antioxidant potential (IC 50 = 19.00 ± 0.37 μg/mL) in terms of free radical scavenging, also for α -amylase inhibition activity with IC 50 values of 17.39 ± 0.92 μg/mL. The molecular docking analysis and the drug-likeness prediction of the major selected compounds explained the significant anti- α -amylase activity of the studied extracts. The obtained analysis and results suggest that F. tunetana extracts could be promising candidates to develop a new generation of efficient and especially safe antidiabetic treatments. [Display omitted] • 38 phytochemicals were quantified in Ferula tunetana extracts by HPLC-MS/MS method. • Total phenolic and flavonoid contents in seed and leaf extracts were estimated. • The studied extracts exhibited good anti- α -amylase and antioxidant activities. • The molecular docking of main components validated the strong antidiabetic effects. • The drug-likeness proprieties of the major compounds were predicted. [ABSTRACT FROM AUTHOR]

Oxidative stress is closely related to cancer aspects, such as the induction of gene mutations resulting from cellular injury and the effects on transcription and signal transduction factors. In addition, antibiotic resistance is also linked with oxidative stress, which could contribute to the selection of resistant bacterial strains. With this in mind, and considering that essential oils are well known to display antioxidant, antimicrobial, and cytotoxic activities, this study was destined to investigate the chemical composition and to screen these properties for the root essential oil (REO) of the Tunisian endemic species Ferula tunetana Pomel ex Batt. The REO GC/MS analysis led to the identification of nine compounds, representing 94.5% of the total oil composition. The phytochemical profile of this essential oil (EO) was characterized by the dominance of sesquiterpenes, comprising 11.7% of sesquiterpene hydrocarbons and 82.8% of oxygenated sesquiterpenes. The three major constituents of the EO were caryophyllene oxide (33.9%), α-cyperone (13.9%), and 14-hydroxy-9-epi-(E)-caryophyllene (12.3%). REO showed a good antioxidant potential against DPPH (IC50 = 30.13 ± 0.28 μg/mL), O2•- (IC50 = 42.87 ± 0.81 μg/mL) and H2O2 (IC50 = 48.03 ± 1.21 μg/mL). Additionally, the antimicrobial activity results showed that REO had a strong antibacterial potential against all target microbial strains, including five Gram-negative, six Gram-positive bacteria, and two Candida species (MICs = 0.039–0.625 mg/mL). Furthermore, the extracted EO was found to have good cytotoxic properties against five human cell lines viz. HT-29, HCT-116, HeLa, A549 and U937, with IC50 values ranging from 3.37 ± 0.02 to 46.66 ± 1.22 μg/mL. The main REO constituents were docked to the human DNA topoisomerase IIα enzyme and the in vitro cellular toxicities were rationalized. The drug-likeness of the main compounds identified in the studied EO was predicted. Overall, the results of the current study prove that the EO of F. tunetana roots has a noteworthy antioxidant potential and represents an interesting candidate to treat infectious diseases and cancer.

A novel series of bis- (Abdelhamid et al., 2017; Banerjee et al., 2018; Bharanidharan et al., 2022)thiadiazoles was synthesized from the reaction of precursor dimethyl 2,2′-(1,2-diphenylethane-1,2-diylidene)-bis(hydrazine-1-carbodithioate) and hydrazonyl chlorides in ethanol under ultrasonic irradiation. Spectral tools (IR. NMR, MS, elemental analyses, molecular dynamic simulation, DFT and LUMO and HOMO) were used to elucidate the structure of the isolated products. Molecular docking for the precursor, 3 and ligands 6a-i to two COVID-19 important proteins Mpro and RdRp was compared with two approved drugs, Remdesivir and Ivermectin. The binding affinity varied between the ligands and the drugs. The highest recorded binding affinity of 6c with Mpro was (−9.2 kcal/mol), followed by 6b and 6a, (−8.9 and −8.5 kcal/mol), respectively. The lowest recorded binding affinity was (−7.0 kcal/mol) for 6 g. In comparison, the approved drugs showed binding affinity (−7.4 and −7.7 kcal/mol), for Remdesivir and Ivermectin, respectively, which are within the range of the binding affinity of our ligands. The binding affinity of the approved drug Ivermectin against RdRp recoded the highest (−8.6 kcal/mol), followed by 6a, 6 h, and 6i are the same have (−8.2 kcal/mol). The lowest reading was found for compound 3 ligand (−6.3 kcal/mol). On the other side, the amino acids also differed between the compounds studied in this project for both the viral proteins. The ligand 6a forms three H-bonds with Thr 319(A), Sr 255(A) and Arg 457(A), whereas Ivermectin forms three H-bonds with His 41(A), Gly143(A) and Gln 18(A) for viral Mpro. The RdRp amino acids residues could be divided into four groups based on the amino acids that interact with hydrogen or hydrophobic interactions. The first group contained 6d, 6b, 6 g, and Remdesivir with 1–4 hydrogen bonds and hydrophobic interactions 1 to 10. Group 2 is 6a and 6f exhibited 1 and 3 hydrogen bonds and 15 and 14 hydrophobic interactions. Group 3 has 6e and Ivermectin shows 4 and 3 hydrogen bonds, respectively and 11 hydrophobic interactions for both compounds. The last group contains ligands 3, 6c, 6 h, and 6i gave 1–3 hydrogen bonds and 6c and 3 recorded the highest number of hydrophobic interactions, 14 for both 6c and 6 h. Pro Tox-II estimated compounds’ activities as Hepatoxic, Carcinogenic and Mutagenic, revealing that 6f-h were inactive in all five similar to that found with Remdesivir and Ivermectin. The drug-likeness prediction was carried out by studying physicochemical properties, lipophilicity, size, polarity, insolubility, unsaturation, and flexibility. Generally, some properties of the ligands were comparable to that of the standards used in this study, Remdesivir and Ivermectin.

• The flowers of Citharexylum spinosum L. was investigated phytochemically. • Verbascoside, apigenin and four rare flavone glucosides were isolated by preparative HPLC. • The isolated compounds exhibited a promising in vitro anti- α- amylase activity. • The in silico molecular docking of the isolated molecules validated the strong antidiabetic effects. • The drug-likeness properties of the studied compounds were predicted. Human concern for its public health has been a cornerstone since ancient times, with humans exploring natural resources in their environment for medicinal purposes. Plants have long served as the primary source of medicinal compounds, reflecting centuries of exploration and experimentation. Today, leveraging cognitive and technological advancements, researchers continue to deepen their studies towards achieving optimal health conditions. In pursuit of antihyperglycemic phyto-alternatives, a phytochemical investigation of EtOAc and n -BuOH flower extracts of Citharexylum spinosum L. yielded four rare flavone glucosides viz. cirsilineol 4′-glucoside, jaceoside, 5,4′-dihydroxy-7,3′-dimethoxyflavone 6-glucoside and pedaliin. Additionally, the flavone aglycone apigenin, and the phenylethanoid glycoside verbascoside were isolated. The flavonoid compounds were isolated for the first time from C. spinosum tree. The extracts underwent silica gel column chromatography for simplification, followed by compound purification using preparative HPLC. Molecular structures were elucidated through NMR spectroscopic experiments, spectrometric ESI-HRMS analysis, and comparisons with existing literature data. Subsequently, extracts and isolated compounds were evaluated for their antihyperglycemic activities by assessing their ability to inhibit α-amylase enzymatic activity. EtOAc and n -BuOH extracts displayed important anti-α-amylase properties with IC 50 values of 52.5 ± 1.2 and 36.3 ± 1.1 µg/mL, respectively. The results demonstrated promising inhibitory properties of the α-amylase enzyme by the polyphenols isolated in this study. IC 50 values ranged from 12.8 ± 0.1 to 23.2 ± 0.1 µM for the isolated compounds, comparable to the reference standard acarbose (IC 50 = 12.3 ± 0.1 µM). Furthermore, a structure-activity relationship study was conducted, with all isolated molecules docked to the α-amylase enzyme (PDB: 7TAA) and their drug-likeness properties predicted. [Display omitted] [ABSTRACT FROM AUTHOR]

A series of 3-amino-substituted rutacecarpine derivatives were synthesized to identify novel multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD). Biological evaluation showed that most of the synthesized compounds inhibited butyrylcholinesterase (BuChE) and exerted antioxidant effects. Among the synthesized compounds, 6n was subjected to further biological evaluation. Lineweaver–Burk plotting and molecular modeling illustrated that 6n bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CAS) of BuChE. Furthermore, 6n modulated Aβ aggregation; chelated biometals; presented good absorption, distribution, metabolism, excretion, and toxicity properties; and showed remarkable neuroprotective activity. Previous research has shown that the optimized compound 6n has considerable potential for development as an MTDL for the treatment of AD. Image 1 • Compound 6n presented better inhibitory activity and selective effect on BuChE. • Compound 6n inhibited ROS formation and displayed antioxidant effects. • Compound 6n displayed self-mediated Aβ aggregation inhibition and selective Cu2+ chelating property. • Compound 6n had good drug-likeness and great neuroprotection. • Compound 6n was considered to be a promising MTDL for the treatment of AD. [ABSTRACT FROM AUTHOR]

Leukemia is a blood or bone marrow cancer with increasing incidence in developed regions of the world. Currently, there is an ongoing need for novel and safe anti-leukemic agents, as no fully effective chemotherapy is available to treat this life-threatening disease. Herein, are reported the isolation, structural elucidation, and anti-leukemic evaluation of twenty-nine withanolide-type steroids (1–29) from Withania aristata. Among them, the new isolated withanolides, withaperoxidins A–D (1–4) have an unusual six-membered cyclic peroxide moiety on the withasteroid skeleton as a structural novelty. Their structures have been elucidated by means of spectroscopic analyses, including 2D NMR experiments. In addition, extensive structure–activity relationships and in silico ADME studies were employed to understand the pharmacophore and pharmacokinetic properties of this series of withasteroids. Compounds 15, 16, and 22 together with withaferin A (14) were identified as having improved antiproliferative effect (IC50 ranging from 0.2 to 0.7 μM) on human leukemia HL-60 cell lines compared with the reference drug, etoposide. This cytotoxic potency was also coupled with good selectivity index (SI 33.0–9.2) on non-tumoral Vero cell line and in silico drug likeness. These findings revealed that these natural withasteroids are potential candidates as chemotherapeutic agents in the treatment of leukemia.

Oxidative stress is closely related to cancer aspects, such as the induction of gene mutations resulting from cellular injury and the effects on transcription and signal transduction factors. In addition, antibiotic resistance is also linked with oxidative stress, which could contribute to the selection of resistant bacterial strains. With this in mind, and considering that essential oils are well known to display antioxidant, antimicrobial, and cytotoxic activities, this study was destined to investigate the chemical composition and to screen these properties for the root essential oil (REO) of the Tunisian endemic species Ferula tunetana Pomel ex Batt. The REO GC/MS analysis led to the identification of nine compounds, representing 94.5% of the total oil composition. The phytochemical profile of this essential oil (EO) was characterized by the dominance of sesquiterpenes, comprising 11.7% of sesquiterpene hydrocarbons and 82.8% of oxygenated sesquiterpenes. The three major constituents of the EO were caryophyllene oxide (33.9%), α -cyperone (13.9%), and 14-hydroxy-9- epi -(E)-caryophyllene (12.3%). REO showed a good antioxidant potential against DPPH (IC 50 = 30.13 ± 0.28 μg/mL), O 2 •- (IC 50 = 42.87 ± 0.81 μg/mL) and H 2 O 2 (IC 50 = 48.03 ± 1.21 μg/mL). Additionally, the antimicrobial activity results showed that REO had a strong antibacterial potential against all target microbial strains, including five Gram-negative, six Gram-positive bacteria, and two Candida species (MICs = 0.039–0.625 mg/mL). Furthermore, the extracted EO was found to have good cytotoxic properties against five human cell lines viz. HT-29, HCT-116, HeLa, A549 and U937, with IC 50 values ranging from 3.37 ± 0.02 to 46.66 ± 1.22 μg/mL. The main REO constituents were docked to the human DNA topoisomerase II α enzyme and the in vitro cellular toxicities were rationalized. The drug-likeness of the main compounds identified in the studied EO was predicted. Overall, the results of the current study prove that the EO of F. tunetana roots has a noteworthy antioxidant potential and represents an interesting candidate to treat infectious diseases and cancer. [ABSTRACT FROM AUTHOR]

A compound that could inhibit multiple targets associated with SARS-CoV-2 infection would prove to be a drug of choice against the virus. Human receptor-ACE2, receptor binding domain (RBD) of SARS-CoV-2 S-protein, Papain-like protein of SARS-CoV-2 (PLpro), reverse transcriptase of SARS-CoV-2 (RdRp) were chosen for in silico study. A set of previously synthesized compounds (1 – 5) were docked into the active sites of the targets. Based on the docking score, ligand efficiency, binding free energy, and dissociation constants for a definite conformational position of the ligand, inhibitory potentials of the compounds were measured. The stability of the protein–ligand (P-L) complex was validated in silico by using molecular dynamics simulations using the YASARA suit. Moreover, the pharmacokinetic properties, FMO and NBO analysis were performed for ranking the potentiality of the compounds as drug. The geometry optimizations and electronic structures were investigated using DFT. As per the study, compound- 5 has the best binding affinity against all four targets. Moreover, compounds 1, 3 and 5 are less toxic and can be considered for oral consumption. [ABSTRACT FROM AUTHOR]

Automated lead optimization helper application (ALOHA) is a novel fitness scoring approach for small molecule lead optimization. ALOHA employs a series of generalized Bayesian models trained from public and proprietary pharmacokinetic, absorption, distribution, metabolism, and excretion, and toxicology data to determine regions of chemical space that are likely to have excellent drug-like properties. The input to ALOHA is a list of molecules, and the output is a set of individual probabilities as well as an overall probability that each of the molecules will pass a panel of user selected assays. In addition to providing a summary of how and when to apply ALOHA, this paper will discuss the validation of ALOHA's Bayesian models and probability fusion approach. Most notably, ALOHA is demonstrated to discriminate between members of the same chemical series with strong statistical significance, suggesting that ALOHA can be used effectively to select compound candidates for synthesis and progression at the lead optimization stage of drug discovery. [ABSTRACT FROM AUTHOR]

A novel series of bis- (Abdelhamid et al., 2017, Banerjee et al., 2018, Bharanidharan et al., 2022)thiadiazoles was synthesized from the reaction of precursor dimethyl 2,2'-(1,2-diphenylethane-1,2-diylidene)-bis(hydrazine-1-carbodithioate) and hydrazonyl chlorides in ethanol under ultrasonic irradiation. Spectral tools (IR. NMR, MS, elemental analyses, molecular dynamic simulation, DFT and LUMO and HOMO) were used to elucidate the structure of the isolated products. Molecular docking for the precursor, 3 and ligands 6a - i to two COVID-19 important proteins M pro and RdRp was compared with two approved drugs, Remdesivir and Ivermectin. The binding affinity varied between the ligands and the drugs. The highest recorded binding affinity of 6c with M pro was (-9.2 kcal/mol), followed by 6b and 6a, (-8.9 and -8.5 kcal/mol), respectively. The lowest recorded binding affinity was (-7.0 kcal/mol) for 6 g . In comparison, the approved drugs showed binding affinity (-7.4 and -7.7 kcal/mol), for Remdesivir and Ivermectin, respectively, which are within the range of the binding affinity of our ligands. The binding affinity of the approved drug Ivermectin against RdRp recoded the highest (-8.6 kcal/mol), followed by 6a , 6 h , and 6i are the same have (-8.2 kcal/mol). The lowest reading was found for compound 3 ligand (-6.3 kcal/mol). On the other side, the amino acids also differed between the compounds studied in this project for both the viral proteins. The ligand 6a forms three H-bonds with Thr 319(A), Sr 255(A) and Arg 457(A), whereas Ivermectin forms three H-bonds with His 41(A), Gly143(A) and Gln 18(A) for viral M pro . The RdRp amino acids residues could be divided into four groups based on the amino acids that interact with hydrogen or hydrophobic interactions. The first group contained 6d , 6b , 6 g, and Remdesivir with 1-4 hydrogen bonds and hydrophobic interactions 1 to 10. Group 2 is 6a and 6f exhibited 1 and 3 hydrogen bonds and 15 and 14 hydrophobic interactions. Group 3 has 6e and Ivermectin shows 4 and 3 hydrogen bonds, respectively and 11 hydrophobic interactions for both compounds. The last group contains ligands 3 , 6c , 6 h, and 6i gave 1-3 hydrogen bonds and 6c and 3 recorded the highest number of hydrophobic interactions, 14 for both 6c and 6 h . Pro Tox-II estimated compounds' activities as Hepatoxic, Carcinogenic and Mutagenic, revealing that 6f-h were inactive in all five similar to that found with Remdesivir and Ivermectin. The drug-likeness prediction was carried out by studying physicochemical properties, lipophilicity, size, polarity, insolubility, unsaturation, and flexibility. Generally, some properties of the ligands were comparable to that of the standards used in this study, Remdesivir and Ivermectin., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Leukemia is a blood or bone marrow cancer with increasing incidence in developed regions of the world. Currently, there is an ongoing need for novel and safe anti-leukemic agents, as no fully effective chemotherapy is available to treat this life-threatening disease. Herein, are reported the isolation, structural elucidation, and anti-leukemic evaluation of twenty-nine withanolide-type steroids (1–29) from Withania aristata. Among them, the new isolated withanolides, withaperoxidins A–D (1–4) have an unusual six-membered cyclic peroxide moiety on the withasteroid skeleton as a structural novelty. Their structures have been elucidated by means of spectroscopic analyses, including 2D NMR experiments. In addition, extensive structure–activity relationships and in silico ADME studies were employed to understand the pharmacophore and pharmacokinetic properties of this series of withasteroids. Compounds 15, 16, and 22 together with withaferin A (14) were identified as having improved antiproliferative effect (IC50 ranging from 0.2 to 0.7 μM) on human leukemia HL-60 cell lines compared with the reference drug, etoposide. This cytotoxic potency was also coupled with good selectivity index (SI 33.0–9.2) on non-tumoral Vero cell line and in silico drug likeness. These findings revealed that these natural withasteroids are potential candidates as chemotherapeutic agents in the treatment of leukemia. [ABSTRACT FROM AUTHOR]