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The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease quickly spreads due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties and computer-aided drug design (in silico studies) for optimizing anti-SARS-CoV-2 hits/leads. [ABSTRACT FROM AUTHOR]

New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties. [ABSTRACT FROM AUTHOR]

Azomethine ylides are nitrogen-based three-atom components commonly used in [3+2]-cycloaddition reactions with various unsaturated 2π-electron components. These reactions are highly regio- and stereoselective and have attracted the attention of organic chemists with respect to the construction of diverse heterocycles potentially bearing four new contiguous stereogenic centers. This review article complies the most important [3+2]-cycloaddition reactions of azomethine ylides with various olefinic, unsaturated 2π-electron components (acyclic, alicyclic, heterocyclic, and exocyclic ones) reported over the past two decades. [ABSTRACT FROM AUTHOR]

Spirooxindoles occupy an important place in heterocyclic chemistry. Many natural spirooxindole-containing compounds have been identified as bio-promising agents. Synthetic analogs have also been synthesized utilizing different pathways. The present article summarizes the recent development of both natural and synthetic spirooxindole-containing compounds prepared from isatin or its derivatives reported in the last five years. The spirooxindoles are categorized based on their mentioned biological properties. [ABSTRACT FROM AUTHOR]

Ursolic acid (UA) is a pentacyclic triterpene isolated from a large variety of vegetables, fruits and many traditional medicinal plants. It is a structural isomer of Oleanolic Acid. The medicinal application of UA has been explored extensively over the last two decades. The diverse pharmacological properties of UA include anti-inflammatory, antimicrobial, antiviral, antioxidant, anti-proliferative, etc. Especially, UA holds a promising position, potentially, as a cancer preventive and therapeutic agent due to its relatively non-toxic properties against normal cells but its antioxidant and antiproliferative activities against cancer cells. Cell culture studies have shown interference of UA with multiple pharmacological and molecular targets that play a critical role in many cells signaling pathways. Although UA is considered a privileged natural product, its clinical applications are limited due to its low absorption through the gastro-intestinal track and rapid elimination. The low bioavailability of UA limits its use as a therapeutic drug. To overcome these drawbacks and utilize the importance of the scaffold, many researchers have been engaged in designing and developing synthetic analogs of UA via structural modifications. This present review summarizes the synthetic UA analogs and their cytotoxic antiproliferative properties reported in the last two decades. [ABSTRACT FROM AUTHOR]

3,5‐Di[(E)‐arylidene]‐1‐[3‐(4‐methylpiperazin‐1‐yl)alkyl]piperidin‐4‐ones 7 a−k were synthesized through dehydrohalogenation of 1‐(2‐chloroacyl)piperidin‐4‐ones 5 a−k with N‐methylpiperazine (6). High antiproliferation potencies were observed by most of the synthesized agents against both HCT116 (colon) and MCF7 (breast) cancer cell lines relative to the standard references (sunitinib and 5‐fluorouracil). The synthesized agents are of dual activity against topoisomerases I and IIα however, with higher efficacy against topoisomerase IIα rather than topoisomerase I. Flow‐cytometry cell cycle studies support the observed antiproliferation properties and exhibit the capability of 1‐(2‐chloroacetyl)‐3,5‐bis[(E)‐4‐chlorobenzylidene]piperidin‐4‐one (5 e) and 3,5‐bis[(E)‐4‐bromobenzylidene]‐1‐[2‐(4‐methylpiperazin‐1‐yl)acetyl]piperidin‐4‐one (7 g) to arrest the HCT116 cell cycle progression at G1/S and G1 phases, respectively. Noticeable anti‐SARS‐CoV‐2 properties were observed by many synthesized agents. 3,5‐Bis[(E)‐4‐chlorobenzylidene]‐1‐[3‐(4‐methylpiperazin‐1‐yl)propanoyl]piperidin‐4‐one (7 f) is the most effective anti‐SARS‐CoV‐2 synthesized with high SI. Applicability of the highly effective candidates synthesized as antitumor and anti‐SARS‐CoV‐2 is due to the safety observations against normal (RPE1 and VERO‐E6) cells. QSAR models validated internally and externally, support their possibility for optimizing more hits/leads. [ABSTRACT FROM AUTHOR]

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2′-pyrrolidine-3′,3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties. [ABSTRACT FROM AUTHOR]

Curcumin (CUR) has received great attention over the past two decades due to its anticancer, anti-inflammatory, and antioxidant properties. Similarly, Dichloroacetate (DCA), an pyruvate dehydrogenase kinase 1 (PKD1) inhibitor, has gained huge attention as a potential anticancer drug. However, the clinical utility of these two agents is very limited because of the poor bioavailability and unsolicited side effects, respectively. We have synthesized fusion conjugates of CUR and DCA with an amino acids linker to overcome these limitations by utilizing the molecular hybridization approach. The molecular docking studies showed the potential targets of Curcumin-Modified Conjugates (CMCs) in breast cancer cells. We synthesized six hybrid conjugates named CMC1-6. These six CMC conjugates do not show any significant toxicity in a human normal immortalized mammary epithelial cell line (MCF10A) in vitro and C57BL/6 mice in vivo. However, treatment with CMC1 and CMC2 significantly reduced the growth and clonogenic survival by colony-formation assays in several human breast cancer cells (BC). Treatment by oral gavage of a transgenic mouse BC and metastatic BC tumor-bearing mice with CMC2 significantly reduced tumor growth and metastasis. Overall, our study provides strong evidence that CUR and DCA conjugates have a significant anticancer properties at a sub-micromolar concentration and overcome the clinical limitation of using CUR and DCA as potential anticancer drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced urinary bladder cancer (BCa) is characterized by rapid progression and development of therapy resistance. Despite all the available therapies, the five-year survival of metastatic BCa is a dismal 8% or lower. Many conjugates and additives of the natural polyphenol curcumin were developed and tested for potential therapeutic for cancers, with little success in vivo due to their rapid elimination and poor tissue penetrance. We tested a novel molecular hybrid CMC-2 composed of a curcumin scaffold conjugated to two dichloroacetate and glycine molecules. CMC-2 showed significantly higher antiproliferative and anti-survival activities against BCa than its parent compounds. Further, it was equally effective against chemotherapy-naïve and multidrug-resistant BCas (MDR-BCa). When tested in vivo using BCa xenograft in athymic mice, CMC-2 significantly delayed tumor growth without systemic toxicity. The mechanism of anticancer activity of CMC-2 was the induction of excessive oxidative stress in the cancer cells, leading to apoptotic cell death. These results show the potential of CMC-2 as a nontoxic oral treatment for high-grade bladder cancers. Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10–15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers. [ABSTRACT FROM AUTHOR]

A new synthetic protocol for the synthesis of 1H‐benzotriazole‐1‐carboximidamides starting from aryl amines in presence of acylbenzotriazole has been reported. The versatile guanylating agents could be an efficient synthetic tool for the synthesis of various guanidines. The present approach enables all possible variations of the substituents at different positions of the products. Single crystal of compound 4e was obtained by recrystallization from suitable solvent systems for X‐ray and DFT studies. The reaction goes faster and yields more product with higher purity when Cbz protected aminoacyl benzotriazole used instead of aryl benzotriazole for the synthesis of the 1H‐benzotriazole‐1‐carboximidamides. Computational studies were carried out to elucidate the energy profile and transition states to support the experimental data. Short reaction time, simple workup, high yields, and mild conditions are the key advantages of this protocol. [ABSTRACT FROM AUTHOR]

A series of new fluoroquinolone conjugates 8a–g and 9a–f were synthesized via benzotriazole‐mediated synthetic approach with good yield and purity. Some of the synthesized analogs exhibited significant antibacterial properties against Escherichia coli and Staphylococcus aureus with potency higher than that of the parent drugs through in vitro standard bioassay procedure (conjugates 8c and 8d reveal antimicrobial properties with potency 1.9, 61.9, 20.7 and 2.4, 37.1, 8.3 folds relative to the parent antibiotic 6 against E. coli, S. aureus, and Enterococcus faecalis, respectively). The observed experimental data were supported by enzymatic DNA gyrase inhibitory property. Developed BMLR‐QSAR model validates the observed experimental data and recognizes the parameters responsible for the enhanced antibacterial properties. [ABSTRACT FROM AUTHOR]

Pyridyloxy-directed Ir(III)-catalyzed diacylmethylation of protected tyrosines was achieved with alkyl and (hetero)aryl sulfoxonium ylides, furnishing tyrosine-based unnatural amino acids in good yields. Furthermore, the late stage exemplification of the strategy was successfully accomplished in tyrosine-containing dipeptides, tripeptides and tetrapeptides in moderate yields. This methodology is distinguished by its site-selectivity, tolerance of sensitive functional groups, scalability, and retention of the chiral configuration for tyrosine motifs. [ABSTRACT FROM AUTHOR]

Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the fight against cancer. This review consolidates recent advancements in developing natural and synthetic indolyl analogs, highlighting their antiproliferative activities against various cancer types over the past five years. These analogs are categorized based on their efficacy against common cancer types, supported by biochemical assays demonstrating their antiproliferative properties. In this review, emphasis is placed on elucidating the mechanisms of action of these compounds. Given the limitations of conventional cancer therapies, developing targeted therapeutics with enhanced selectivity and reduced side effects remains a critical focus in oncological research. [ABSTRACT FROM AUTHOR]

Microwave-assisted reaction of 3,5-bis((E)-ylidene)-1-phosphonate-4-piperidones 3a‒g with azomethine ylide (produced through interaction of isatins 4 and sarcosine 5) cycloaddition afforded the corresponding (dispiro[indoline-3,2′-pyrrolidine-3′,3″-piperidin]-1″-yl)phosphonates 6a‒l in excellent yields (80–95%). Structure of the synthesized agents was evidenced by single crystal X-ray studies of 6d , 6i and 6l. Some of the synthesized agents revealed promising anti-SARS-CoV-2 properties in the viral infected Vero-E6 cell technique with noticeable selectivity indices. Compounds 6g and 6b are the most promising agents synthesized (R = 4-BrC 6 H 4 , Ph; R' = H, Cl, respectively) with considerable selectivity index values. Mpro-SARS-CoV-2 inhibitory properties supported the anti-SARS-CoV-2 observations of the potent analogs synthesized. Molecular docking studies (PDB ID: 7C8U) are consistent with the Mpro inhibitory properties. The presumed mode of action was supported by both experimentally investigated Mpro-SARS-CoV-2 inhibitory properties and explained by docking observations. Spiroindoles bearing phosphonate group were regioselectively synthesized exhibiting promising Mpro-SARS-CoV-2 properties. [Display omitted] • Spiroindoles bearing phosphonate group were synthesized. • Single crystal X-ray studies evidenced the structure. • Promising anti-SARS-CoV-2 properties were exhibited by the synthesized agents. • Mpro-SARS-CoV-2 inhibitory properties were revealed by the synthesized agents. • Docking studies supported the biochemical properties revealed. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 pandemic is considered as one of the most disastrous pandemics for human health and the world economy. RNA-dependent RNA polymerase (RdRp) is one of the key enzymes that control viral replication. RdRp is an attractive and promising therapeutic target for the treatment of SARS-CoV-2 disease. It has attracted much interest of medicinal chemists, especially after the approval of Remdesivir. This study highlights the most promising SARS-CoV-2 RdRp repurposed drugs in addition to natural and synthetic agents. Although many in silico predicted agents have been developed, the lack of in vitro and in vivo experimental data has hindered their application in drug discovery programs. [Display omitted] • This article provides an overview of RdRp inhibitors targeting SARS-CoV-2. • We categorized repurposed drugs, natural products, and synthetic compounds for better understanding. • The compiled drug-like molecules will enable researchers in this field to develop a new generation of RdRp inhibitors. • Molecular docking and ADME-Tox data could be used as additional resources for the new drug development process. [ABSTRACT FROM AUTHOR]

Facile synthetic pathway for nicotinonitriles 5a‒o , 7a‒i was demonstrated through reaction of ketones 4a‒k , 6a‒f with ylidenemalononitrile 3 in the presence of sodium alkoxide. Meanwhile, nucleophilic attack of amines on 2-bromonicotinonitrile 9 (obtained through reaction of propenone 8 with malononitrile, followed by bromination with bromine in acetic acid) afforded 3-pyridinecarbonitriles 11a‒d . Single crystal X-ray of compound 7i reveals the monoclinic space group C2/c with 8 molecules per unit cell. Optimized structure of 7i [DFT/B3LYP, 6-31G(d,p)] shows close correlations to that of X-ray study. Compound 5l seems superior among all the synthesized analogues exhibiting bronchodilation properties about three folds potency compared to theophylline (standard reference) through pre-contracted tracheal rings with histamine standard method. Also compound 5a reveals promising observations (about two folds potency of the standard reference). Molecular modeling studies (3D-pharmacophore and 2D-QSAR) supported the observed biological properties. [ABSTRACT FROM AUTHOR]

Click chemistry technique led to novel 1,2,3-triazole-quinine conjugates 8a – g , 10a – o , 11a – h and 13 utilizing benzotriazole-mediated synthetic approach with excellent yields. Some of the synthesized analogs ( 11a , 11d – h ) exhibited antimalarial properties against Plasmodium falciparum strain 3D7 with potency higher than that of quinine (standard reference used) through in vitro standard procedure bio-assay. Statistically significant BMLR-QSAR model describes the bio-properties, validates the observed biological observations and identifies the most important parameters governing bio-activity. [ABSTRACT FROM AUTHOR]

Novel fluoroquinolone–pyrazine conjugates 7a – h with amino acid linkers were synthesized in good yields utilizing benzotriazole chemistry. Antimicrobial bioassay showed that the synthesized bis-conjugates have antimicrobial properties comparable to the parent drugs. Compound 7h showed superior antibacterial activity against Staphylococcus aureus and Streptococcus pyogenes (MIC = 74.6 μM and 149.3 μM, respectively). This matched well with the estimated values obtained from 3D-pharmacophore and 2D-QSAR studies (MIC = 67 μM and 92.9 μM, respectively). [ABSTRACT FROM AUTHOR]

Novel, quinolone–fluoroquinolone conjugates 10a – f , 11a – f , 13a – f and 14a – f with amino acid linkers were synthesized in good yields utilizing benzotriazole chemistry. Antibacterial bioassay showed the synthesized bis-conjugates exhibit anti-bacterial properties comparable with the parent drugs. [ABSTRACT FROM AUTHOR]

Chiral peptides and iso -peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski’s Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso -peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results. [ABSTRACT FROM AUTHOR]

Malaria is a tropical disease, prevalent in Southeast Asia and Africa, resulting in over half a million deaths annually; efforts to develop new antimalarial agents are therefore particularly important. Quinine continues to play a role in the fight against malaria, but quinoline derivatives are more widely used. Drugs based on the quinoline scaffold include chloroquine and primaquine, which are able to act against the blood and liver stages of the parasite's life cycle. The purpose of this review is to discuss reported biologically active compounds based on either the quinine or quinoline scaffold that may have enhanced antimalarial activity. The review emphasises hybrid molecules, and covers advances made in the last five years. The review is divided into three sections: modifications to the quinine scaffold, modifications to aminoquinolines and finally metal-containing antimalarial compounds. [ABSTRACT FROM AUTHOR]

Novel, mesalazine, metronidazole conjugates 6a – e with amino acid linkers were synthesized utilizing benzotriazole chemistry. Biological data acquired for all the novel bis-conjugates showed (a) some bis-conjugates exhibit comparable anti-inflammatory activity with parent drugs and (b) the potent bis-conjugates show no visible stomach lesions. 3D-pharmacophore and 2D-QSAR modeling support the observed bio-properties. [ABSTRACT FROM AUTHOR]

N-Acyl threonine isopeptides undergo acyl transfer in chemical ligations via 5-, 8-, 9- and 10-membered cyclic transition states to yield natural peptides, representing the first examples of successful isopeptide ligations from N-acyl threonine units. [ABSTRACT FROM AUTHOR]

Two approaches to the synthesis of oxygen-bridged tetrahydropyridones have been developed. In the first approach, substituted pyrido[4,3-g][1,3]oxazocines derivatives were prepared by diastereoselective one-pot reactions of substituted 7-azacoumarins with enolizable ketones and non-bulky primary amines. In the second one, 3-amido-7-azacoumarins were reacted with enolizable ketones in the presence of a base to form diastereomerically pure pyrido[4,3-g][1,3]oxazocines. [ABSTRACT FROM AUTHOR]

Benzotriazole-mediated synthesis provides novel fluorescent- labeled amino acid-quinolone antibiotic conjugates in good yields with retention of chirality. The photophysical properties of all the fluorescent-labeled antibiotic conjugates were determined. [ABSTRACT FROM AUTHOR]

Benzotriazole-activated biotin was utilized as a versatile building block for the efficient and convenient synthesis of novel biotin conjugates with quinolone antibiotics via amino acid linkers under microwave irradiation. The products are obtained in yields of 70-91% with retention of chirality. [ABSTRACT FROM AUTHOR]

Peptidesare ubiquitous in nature where they play crucial roles as catalysts(enzymes), cell membrane ion transporters, and structural elements(proteins) within biological systems. In addition, both linear andcyclic peptides have found use as pharmaceuticals and components ofvarious conjugate molecular systems. Small wonder then that chemiststhroughout the ages have sought to mimic nature by synthesis of theamide polymers known as peptides and proteins. [ABSTRACT FROM AUTHOR]

Abstract: Amino acid conjugates of quinolone, metronidazole and sulfadiazine antibiotics were synthesized in good yields using benzotriazole methodology. All the conjugates were screened for their antibacterial activity using methods adapted from the Clinical and Laboratory Standards Institute. Antibiotic conjugates were tested for activity in four medically relevant organisms; Staphylococcus aureus (RN4220), Escherichia coli (DH5α), Pseudomonas aeruginosa (PAO1), and Bacillus subtilis (168). Several antibiotic conjugates show promising results against several of the strains screened. [Copyright &y& Elsevier]

Protected amino/peptide thioacids have been synthesized in pure form in excellent yields and with retention of chirality by using protected aminoacyl- and peptidoylbenzotriazoles as active intermediates. [ABSTRACT FROM AUTHOR]

A convenient synthesis of chiral N-, O-, and S-acyl monoiso- and diisopeptides from di- and tripeptides containing tryptophan, tyrosine, and cysteine units using benzotriazole is reported in solution phase. [ABSTRACT FROM AUTHOR]

A greener protocol for the synthesis of mesalazine conjugates is reported. Mesalazine conjugates are prepared in high yields by a one-pot reaction of mesalazine and aminoacyl/peptidoylbenzotriazoles in water under microwave irradiation. [ABSTRACT FROM AUTHOR]

2-Substituted benzothiazoles were synthesized in excellent yields by a benzotriazole methodology, with the conditions being efficient, green, economical, and suitable for broad applications in medicinal chemistry and the synthesis of specialty chemicals. [ABSTRACT FROM AUTHOR]

Amino acid and peptide conjugates of quinine were synthesized using microwave irradiation in 52-95% yields using benzotriazole methodology. The majority of these conjugates retain in vitro antimalarial activity with IC50 values below 100 n m, similar to quinine. [ABSTRACT FROM AUTHOR]

(α-Benzyloxycarbonyl-aminoacyl)benzotriazolides (Cbz = benzyloxycarbonyl) underwent a coupling reaction with α-hydrazino acids under microwave irradiation to form hybrid hydrazino dipeptides (42-71 %). Chiral acylations of β- N-Cbz-α-hydrazino acylbenzotriazolides were successfully carried out with N -, S-, O-, and C-nucleophiles in yields of 49-88 %. [ABSTRACT FROM AUTHOR]

Efficient syntheses of O-acyl Tyr-peptides allow chemical long-range ligation (O-acyl to N-acyl transfer) via each of 12- to 19-membered cyclic transition states. The results represent the first examples of successful isopeptide ligations starting from O-acyl Tyr-peptides. [ABSTRACT FROM AUTHOR]

Abstract: A series of quinolone derivatives, containing different heterocyclic amines were prepared. Synthesized compounds were evaluated for their in vitro antimicrobial activities against two Gram-positive bacteria, three Gram-negative bacteria as well as four fungi. All the derivatives showed good activity towards Gram-positive bacteria and less activity towards Gram-negative bacteria. They also showed moderate to comparable activity against Aspergillus niger and Candida albicans and low to moderate antifungal activity against Aspergillus fumigatus and Aspergillus flavus. [Copyright &y& Elsevier]

Optimized selective S-acylations of cysteine esters gave intermediates for the synthesis of macrocyclic peptoids by a benzotriazole- based method. [ABSTRACT FROM AUTHOR]

Unprotected S-acylated cysteine isopeptides containing α-, β- or γ-amino acid units have been synthesized, and their conversion to native hexapeptides by S- to the N-terminus ligations involving 17-, 18- and 19-membered cyclic transition states have been demonstrated both experimentally and computationally to be more favorable than intermolecular cross-ligations. [ABSTRACT FROM AUTHOR]

Cbz-(protected)-tri- and tetrapeptide conjugates with steroids, sugars, terpenes, and heterocycles were prepared using Cbz-(protected)-tri- and tetrapeptidoylbenzotriazoles as active intermediates. [ABSTRACT FROM AUTHOR]

A highly efficient synthesis of some novel symmetrical bis spiro-indoles has been achieved by cyclocondensation of hitherto unknown bis Schiff's bases with mercaptoacetic acid in water. The structures of the new compounds have been deduced by elemental analysis and spectral data. GRAPHICAL ABSTRACT [ABSTRACT FROM PUBLISHER]

Abstract: A series of novel spiro[indole-thiazolidine]spiro[indole-pyran] derivatives were synthesized from N-(bromoalkyl)indol-2,3-diones via monospiro-bisindole intermediates; the two indole nuclei being connected via N–(CH2) n –N linker. Synthesized compounds were evaluated for their antimicrobial activities in vitro against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Staphylococcus epidermis), four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumonia) as well as four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Candida albicans) using Cup plate method. Bis spiro-indoles exhibited stronger antibacterial and antifungal efficiency than their corresponding mono spiro-indoles. Compound 10e, the most active derivative was shown to inhibit the growth of all bacterial strains and two fungal strains (A. niger and C. albicans) [Copyright &y& Elsevier]

Series of salicylate-curcumin mimics were synthesized of potential antiproliferative (against A431 and HCT116 cell lines) and anti-SARS-CoV-2 properties. [Display omitted] • Salicylate-curcumin mimics were prepared in a facile pathway. • They reveal promising properties against A431 and HCT116 cell lines. • They are multi-targeted inhibitors against VEGFR-2 and EGFR. • Docking studies support the EGFR inhibitory properties. • Some of them are anti-SARS-CoV-2 with high SI. Series of piperidone-salicylate conjugates were synthesized through the reaction of 3 E ,5 E -bis(arylidene)-4-piperidones with the appropriate acid chloride of acetylsalicylate in the presence of triethylamine. All the synthesized conjugates reveal antiproliferative properties against A431 (squamous skin) cancer cell line with potency higher than that of 5-fluorouracil. Many of the synthesized agents also exhibit promising antiproliferative properties against HCT116 (colon) cancer cell line, of which 5o and 5c are the most effective with 12.9, 9.8 folds potency compared with Sunitinib. Promising activity is also shown against MCF7 (breast) cancer cell line with 1.19, 1.12 folds relative to 5-fluorouracil. PI-flow cytometry of compound 5c supports the arrest of cell cycle at G1-phase. However, compound 5o and Sunitinib arrest the cell cycle at S-phase. The synthesized conjugates can be considered as multi-targeted tyrosine kinase inhibitors due to the promising properties against VEGFR-2 and EGFR in MCF7 and HCT116. CDOCKER studies support the EGFR inhibitory properties. Compounds 5p and 5i possessing thienylidene heterocycle are anti-SARS-CoV-2 with high therapeutic indices. Many of the synthesized agents show enhanced COX-1/2 properties than aspirin with better selectivity index towards COX-2 relative to COX-1. The possible applicability of the potent candidates discovered as antitumor and anti-SARS-CoV-2 is supported by the safe profile against normal (non-cancer, RPE1 and VERO-E6) cells. [ABSTRACT FROM AUTHOR]

Sets of 3-alkenyl-2-oxindoles were synthesized of potential antiproliferative (against PaCa-2 and MCF7cancer cell lines) and promising properties against SARS-CoV-2. [Display omitted] • 3-Alkenyl-2-oxindoles were prepared in a facile synthetic pathway. • The synthesized agents show potent properties against PaCa2 cell line. • CAM assay reveals the anti-angiogenic properties of the targeted agents. • The agents synthesized show multi-targeted inhibitory properties against VEGFR-2 and c-kit. • Antiviral properties against SARS-CoV-2 and high SI were revealed by the synthesized agents. Sets of 3-alkenyl-2-oxindoles (6 , 10 , 13) were synthesized in a facile synthetic pathway through acid dehydration (EtOH/HCl) of the corresponding 3-hydroxy-2-oxoindolines (5 , 9 , 12). Single crystal (10a , c) and powder (12a , 26f) X-ray studies supported the structures. Compounds 6c and 10b are the most effective agents synthesized (about 3.4, 3.3 folds, respectively) against PaCa2 (pancreatic) cancer cell line relative to the standard reference used (Sunitinib). Additionally, compound 10b reveals antiproliferative properties against MCF7 (breast) cancer cell with IC 50 close to that of Sunitinib. CAM testing reveals that compounds 6 and 10 demonstrated qualitative and quantitative decreases in blood vessel count and diameter with efficacy comparable to that of Sunitinib, supporting their anti-angiogenic properties. Kinase inhibitory properties support their multi-targeted inhibitory activities against VEGFR-2 and c-kit in similar behavior to that of Sunitinib. Cell cycle analysis studies utilizing MCF7 exhibit that compound 6b arrests the cell cycle at G1/S phase while, 10b reveals accumulation of the tested cell at S phase. Compounds 6a and 10b reveal potent antiviral properties against SARS-CoV-2 with high selectivity index relative to the standards (hydroxychloroquine, chloroquine). Safe profile of the potent synthesized agents, against normal cells (VERO-E6, RPE1), support the possible development of better hits based on the attained observations. [ABSTRACT FROM AUTHOR]

A series of quinolone-triazole conjugates synthesized as potential antiviral agents for SARS-CoV2. Some of the conjugates are more potent than the standards. [Display omitted] • A set of quinolone-triazole conjugates was designed and synthesized. • Some conjugates show promising antiviral properties against SARS-CoV2. • The selectivity index (SI) of the synthesized potent conjugates better than the reference drugs. • Potential conjugates could be further explored for the development of potential antiviral drug candidates. At present therapeutic options for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are very limited. We designed and synthesized three sets of small molecules using quinoline scaffolds. A series of quinoline conjugates (10a-l, 11a-c, and 12a-e) by incorporating 1,2,3-triazole were synthesized via a modified microwave-assisted click chemistry technique. Among the synthesized conjugates, 4-((1-(2-chlorophenyl)-1 H -1,2,3-triazol-4-yl)methoxy)-6-fluoro-2-(trifluoromethyl)quinoline (10g) and 6-fluoro-4-(2-(1-(4-methoxyphenyl)-1 H -1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)quinoline (12c) show high potency against SARS-CoV-2. The selectivity index (SI) of compounds 10g and 12c also indicates the significant efficacy compared to the reference drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer chemotherapy is dominated by cytotoxic drugs that non-selectively kill proliferating cells by blocking DNA replication and inducing apoptosis. Some natural anticancer products are less toxic to normal, slow-replicating cells but kill aggressive tumor cells. The combination of two structural isomers of pentacyclic triterpenes, oleanolic acid and ursolic acid, showed potent cytotoxic activity in human breast cancer cells in vitro by inducing cytotoxic autophagy at a significantly lower dose than previously reported. They were nontoxic to breast epithelial cells. Their activity was mainly due to the inhibition of AKT-mediated cell survival and the inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, a central regulator of cell metabolism, growth, and proliferation. The compounds were equally effective against ER+ and triple-negative breast cancer cells. Combining low doses of nontoxic inhibitors of PI3k kinase increased the activities of these compounds. In contrast, inhibition of autophagy by 3-methyl adenine annulled their activity, demonstrating that cytotoxic autophagy may be the dominant mechanism of cell death. These compounds have potential for cancer therapy in neoadjuvant or adjuvant settings. Background: Oleanolic acid (OA) and Ursolic acid (UA) are bioactive triterpenoids. Reported activities vary with the dose used for testing their activities in vitro. Studies using doses of ≥20 µM showed apoptosis activities in cancer cells. However, reported drug levels in circulation achieved by oral administration of UA and OA are ≤2 µM, thus limiting their use for treatment or delivering a combination treatment. Materials and Methods: The present report demonstrates the efficacy of OA, UA, and OA + UA on tumor cell-specific cytotoxicity at low doses (5 µM to 10 µM) in breast cancer (BrCa) cell lines MCF7 and MDA-MB231. Results: The data show that both OA and UA killed BrCa cells at low doses, but were significantly less toxic to MCF-12A, a non-tumorigenic cell line. Moreover, OA + UA at ≤10 µM was lethal to BrCa cells. Mechanistic studies unraveled the significant absence of apoptosis, but their cytotoxicity was due to the induction of excessive autophagy at a OA + UA dose of 5 µM each. A link to drug-induced cytotoxic autophagy was established by demonstrating a lack of their cytotoxicity by silencing the autophagy-targeting genes (ATGs), which prevented OA-, UA-, or OA + UA-induced cell death. Further, UA or OA + UA treatment of BrCa cells caused an inhibition of PI3 kinase-mediated phosphorylation of Akt/mTOR, the key pathways that regulate cancer cell survival, metabolism, and proliferation. Discussion: Combinations of a PI3K inhibitor (LY294002) with OA, UA, or OA + UA synergistically inhibited BrCa cell survival. Therefore, the dominance of cytotoxic autophagy by inhibiting PI3K-mediated autophagy may be the primary mechanism of PTT-induced anticancer activity in BrCa cells. Conclusion: These results suggest it would be worthwhile testing combined OA and UA in clinical settings. [ABSTRACT FROM AUTHOR]

The ease of intramolecular N-to N-and O-to N-acyl transfers in (N)-acyl isopeptides and (O)-acyl isopeptides was found to be governed by preorganization rationalized in terms of geometrical and energetic characteristics of the linear isopeptide backbone, which depends on the chain length. Intramolecular hydrogen bonding was found another important factor of reactivity able to stabilize the chemical ligation transition state. [Copyright &y& Elsevier]

A series of curcumin bis-conjugates 3a-q , 5a-k and 6a-k were synthesized in good yields utilizing an optimized reaction condition. We explored the effect of different amino acids and protecting groups on biological activities of curcumin. The conjugates were screened for anti-inflammatory, analgesic and antimicrobial properties. Some of the conjugates showed promising biological observations with a potency comparable with the standard references. The variations in biological properties concerning different amino acids and protecting groups are interesting observations. Effects of the synthesized conjugates on splenocytes and the production of nitric oxide by lipopolysaccharide-stimulated peritoneal macrophages are correlated with the observed anti-inflammatory properties. We have also established the safety profile of the most active conjugates. Robust 2D-QSAR studies supported and validated biological data. A series of curcumin conjugates synthesized as potential pharmacophores. Some of the conjugates are more potent than the standards. Image 1 • A set of curcumin conjugates was designed and synthesized. • Curcumin conjugates show promising analgesic, anti-inflammatory and antimicrobial activity with low cytotoxicity. • 2D-QSAR studies supports the biological data. • Developed QSAR model could be useful tool for new drug development. • Potential conjugates could be further explored for the development of potential prodrug. [ABSTRACT FROM AUTHOR]

Alkaloids found in multiple species, known as 'driver species', are more likely to be included in early-stage drug development due to their high biodiversity compared to rare alkaloids. Many synthetic approaches have been employed to hybridize the natural alkaloids in drug development. Click chemistry is a highly efficient and versatile reaction targeting specific areas, making it a valuable tool for creating complex natural products and diverse molecular structures. It has been used to create hybrid alkaloids that address their limitations and serve as potential drugs that mimic natural products. In this review, we highlight the recent advancements made in modifying alkaloids using click chemistry and their potential medicinal applications. We discuss the significance, current trends, and prospects of click chemistry in natural product-based medicine. Furthermore, we have employed computational methods to evaluate the ADMET properties and drug-like qualities of hybrid molecules. [ABSTRACT FROM AUTHOR]

Benzimidazole is a heterocyclic moiety of immense importance as it acts as a primary "biolinker" in diverse synthetic routes to obtain bioactive compounds. Substituted benzimidazoles are known to possess a varied range of pharmacological applications, namely, anti‐cancer, anti‐diabetic, anti‐inflammatory, and antiviral like anti‐HIV and anti‐fungal. A number of reviews covering the important aspects of benzimidazoles such as pharmacological activities, SAR studies, and well‐known methods of synthesis have appeared in the literature. However, green synthetic methods particularly using transition metal (TM) catalysts and their nanoparticles, although being more viable and extensively applied by researchers in the present scenario, have not been exclusively and expansively reviewed. Besides this, the vital precursors required for knitting the skeleton of benzimidazole are mainly o‐aryldiamines. The conventional synthesis generally involved the condensation of these diamines with carbonyl/carboxylic acid derivatives either via high temperature heating or via adding strong acids, mostly resulting in poor yields or mixtures. However, recent trends are replacing these conditions by mild and green conditions through TM catalysts. Therefore, the current review emphasizes on the recent trends adopted in the synthesis of benzimidazoles using condensation reaction of o‐phenylenediamines and various aldehydes/ester/amide/alcohols with TM in a catalytic role in nanoform and under environmentally benign green conditions. [ABSTRACT FROM AUTHOR]

Review: [89 refs. [ABSTRACT FROM AUTHOR]