Benzofuran–isatin Hybrids: Design,Synthesis, and In Vitro Anti‐cancer Activities

A series of novel benzofuran–isatin hybrids 6a – s tethered through propylene and butylene were designed, synthesized, and evaluated for their in vitro anti‐cancer activities against HepG2 (liver carcinoma), Hela (cervical cancer), A549 (lung adenocarcinoma), DU145 (prostatic cancer), SKOV3 (ovarian carcinoma), MCF‐7 (breast cancer), and drug‐resistant MCF‐7/DOX (doxorubicin‐resistant MCF‐7) human cancer cell lines. The majority of the synthesized hybrids displayed weak to moderate in vitro activities against the tested seven cancer cell lines, but the enriched structure–activity relationship may pave the way for further optimization.     

Design,Synthesis, and Evaluation of Tetraethylene Glycol‐Tethered Isatin–1,2,3‐Triazole–Coumarin Hybrids as Novel Anticancer Agents

We report herein the design and synthesis of a series of novel tetraethylene glycol‐tethered isatin–1,2,3‐triazole–coumarin hybrids and evaluate their in vitro antitumor activities against seven common human cancer cell lines including drug‐resistant cell line. Results revealed that all the synthesized hybrids showed weak to moderate activities against the tested seven cancer cell lines. The structure–activity relationship was also discussed, and the enriched structure–activity relationship may pave the way for further rationale design of this kind of hybrids.     

Design,Synthesis, and In Vitro Anticancer Activities of Diethylene Glycol Tethered Isatin‐1,2,3‐triazole‐coumarin Hybrids

A series of novel diethylene glycol tethered isatin‐1,2,3‐triazole‐coumarin hybrids 9a – l were designed, synthesized, and evaluated for their in vitro anticancer activities against HepG2 (liver carcinoma), Hela (cervical cancer), A549 (lung adenocarcinoma), DU145 (prostatic cancer), SKOV3 (ovarian carcinoma), MCF‐7 (breast cancer), and drug‐resistant MCF‐7/DOX (doxorubicin‐resistant MCF‐7) human cancer cell lines. The results showed that most of the synthesized hybrids exhibited considerable in vitro activities against the tested seven cancer cell lines, and these hybrids can be acted as starting points for further investigation.     

Design,Synthesis, and Evaluation of Tetraethylene Glycol Tethered Ciprofloxacin–Isatin Hybrids as Novel Antitubercular Agents

A new set of tetraethylene glycol tethered ciprofloxacin–isatin hybrids 5a–l with greater lipophilicity than the parent ciprofloxacin was designed, synthesized, and screened for their in vitro antimycobacterial activity against drug‐sensitive Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant MTB strains as well as toxicity in a mammalian VERO cell line. The preliminary results revealed that all hybrids exhibited considerable activity against MTB H₃₇Rv with minimum inhibitory concentration in a range of 0.205–14.186 μg/mL. Especially, hybrid 5a with low cytotoxicity displayed highest activity against both drug‐sensitive MTB H₃₇Rv and two clinically isolates multidrug‐resistant MTB strains, suggesting that it may serve as a new and promising candidate for further study.     

Antiproliferative,Cytotoxic, and Apoptotic Effects of New Benzimidazole Derivatives Bearing Hydrazone Moiety

In order to take the advantages of the anticancer properties of benzimidazoles and hydrazones, we synthesized new 4‐(5‐chloro‐1H‐benzimidazol‐2‐yl)‐benzoic acid benzylidene hydrazide derivatives ( 3a–3t ) and evaluated their anticancer activity against A549 (human lung adenocarcinoma) and MCF‐7 (human breast adenocarcinoma) cells. The structures of the compounds ( 3a–3t ) were confirmed by IR, ¹H‐NMR, ¹³C‐NMR, mass spectroscopy, and elemental analyses. Antiproliferative activities of the compounds were evaluated using MTT assay, BrdU method, and flow cytometric analysis. In addition, with purpose of determining selectivity the cytotoxic activities of the final compounds were screened against healthy NIH3T3 cell line (mouse vembryonic fibroblast cells). Among the tested compounds 3e and 3f showed significant cytotoxic activity against A549 and MCF‐7 cancer cells with an IC₅₀ value of 0.0316 μM. Furthermore, compound 3p showed remarkable cytotoxic activity against MCF‐7 comparing with standard drug cisplatin. Annexin V‐FITC assay also suggested that this compounds induced cell death by apoptosis.     

Design,Synthesis, and Anticancer Activities of Benzofuran–Isatin Hybrids Tethered by Pentylene and Hexylene

Fourteen benzofuran–isatin hybrids 6a – f and 7a – h tethered via alkyl linker (pentylene and hexylene) were designed and synthesized, and hybrids 6c – f and 7a – h were screened for their in vitro anticancer activity against various human cancer cell lines. The majority of the hybrids were active against the tested cancer cells, and the most active hybrids 7g (half maximal inhibitory concentration/IC₅₀: 77.2–88.9 μM) and 7h (IC₅₀: 65.4–89.7 μM), which possessed broad spectrum anticancer activity were as potent as the reference vorinostat (IC₅₀: 64.2–>100 μM) against all tested cancer cell lines, could act as leads for further investigations. The structure–activity relationship is also discussed, and the enriched structure–activity relationship may afford useful information for further rational design of the candidates with higher activity.     

Design,Synthesis and Antifungal Activity of Benzofuran and Its Analogues

Benzofuran has antifungal activity as the inhibitor of N‐myristoyltransferase. Twenty‐nine novel benzofuran‐semicarbazide hybrids were designed and synthesized by principle of drug combinationatory. On this basis, the benzofuran ring was simplified to a resorcinol structure, and sixteen novel 1,3‐dialkoxybenzene‐semicarbazide hybrids were designed and synthesized. All structures of the target compounds were characterized by HRMS and NMR. The in vitro antifungal activity of target compounds was evaluated using the microdilution broth method against eight strains of pathogenic fungi with fluconazole as positive control. According to the results of the target compounds, structure‐activity relationship (SAR) is summarized. The inhibitory activity against the tested strains of simplified compounds ( K01 — K16 ) has different levels improvement compared with compounds Z01 — Z29 . K01 — K16 showed significant antifungal activities against A. fumigatus, C. kruseii, and sensitive C. albicans 5314. Notably, compounds Z20 , Z22 , K10 , K11 and K16 also displayed different activities against two fluconazole‐resistance strains that were isolated from AIDS patients. The minimal inhibitory concentration (MIC) values against fluconazole‐resistant strains were in the range of 2—8 μg/mL and 4—32μg/mL, respectively. Furthermore, molecular docking was performed to investigate the binding affinities and interaction modes between the target compound and N‐myristoyltransferase.     

Design,Synthesis, and In Vitro Anti‐mycobacterial Activities of Propylene Tethered Benzofuran–Isatin Hybrids

A series of novel propylene tethered benzofuran–isatin hybrids 5a–j were designed, synthesized, and assessed for their in vitro anti‐mycobacterial activity against Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant (MDR)‐MTB strains. All hybrids exhibited promising anti‐mycobacterial activities against the tested two pathogens with minimum inhibitory concentration (MIC) ranging from 2 to 32 μg/mL, and the resistance index for a significant part of the hybrids was ≤1, indicating their potential for the treatment of drug‐resistant tuberculosis. Hybrid 5g (MIC: 2 and 4 μg/mL) was found to be the most active against MTB H₃₇Rv and MDR‐MTB, which was eightfold and >32‐fold more active than the first‐line anti‐tuberculosis drugs rifampicin (MIC: 32 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR‐MTB, and it could act as a starting point for further optimization.     

4‐Quinolone Derivatives and Their Activities Against Gram‐negative Pathogens

Gram‐negative pathogens represent a significant global health threat, while the emergency and widespread of drug resistance make the situation even worse. As “privileged building blocks,” 4‐quinolones including fluoroquinolones are mainstays of chemotherapy against various bacterial infections. However, as other antibiotics, the resistance of Gram‐negative bacteria to 4‐quinolones develops rapidly and spreads widely throughout the world. To overcome the resistance and improve the potency, a number of 4‐quinolone derivatives were designed, synthesized, and screened for their in vitro and in vivo activities against representative Gram‐negative pathogens. This review aims to summarize the recent advances made towards the discovery of 4‐quinolone derivatives as anti‐Gram‐negative agents as well as their structure–activity relationship. The enriched structure–activity relationship paves the way to the further rational development of 4‐quinolones with excellent potency against both drug‐susceptible and drug‐resistant Gram‐negative pathogens.     

Propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered Isatin‐coumarin Hybrids: Design,Synthesis, and In Vitro Anti‐tubercular Evaluation

A series of novel propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered isatin‐coumarin hybrids 7a–l that were composed of three anti‐tubercular bioactive substances/pharmacophore coumarin, isatin, and I‐A09 were designed, synthesized, and assessed for their in vitro anti‐tubercular activity against Mycobacterium tuberculosis (MTB) H₃₇Rv. In spite of the hybrids were inactive against the tested MTB H₃₇Rv, the structure–activity relationship was enriched, and these hybrids may act as an ideal starting point for developing new isatin‐coumarin anti‐TB candidates with various linkers.     

Synthesis and Anti‐tumor Evaluation of Novel C‐37 Modified Derivatives of Gambogic Acid

Gambogic acid (GA, 1 ), the most prominent representative of Garcinia natural products, has been reported to be a promising anti‐tumor agent. In order to further explore the structure‐activity relationship of GA and discover novel GA derivatives as anti‐tumor agents, 17 novel C‐37 modified derivatives of GA were synthesized and evaluated for their in vitro anti‐tumor activities against A549, HCT‐116, BGC‐823, HepG2 and MCF‐7 cancer cell lines. Among them, 11 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 8 was almost 5–10 folds more active than GA against A549 and BGC‐823 cell lines with the IC₅₀ values of 0.12 µmol·L^?1 and 0.57 µmol·L^?1, respectively. Chemical modification at C‐37 position of GA by introducing of hydrophilic amines could lead to increased activity and improved drug‐like properties. These findings will enhance our understanding of the structure‐activity relationship (SAR) of GA and lead to the discovery of novel GA derivatives as potential anti‐tumor agents.     

Design,Synthesis and In Vitro Antitubercular Evaluation of Isatin‐ciprofloxacin Hybrids with Hydrogen Bonding Capacity

A series of novel isatin‐ciprofloxacin hybrids inhaling oxime, semicarbazone, and thiosemicarbazone groups with hydrogen bonding capacity were designed, synthesized, and evaluated for their in vitro antitubercular activities against Mycobacterium tuberculosis (MTB) H37Rv and multidrug‐resistant‐TB (MDR‐TB). All hybrids endowed with potential activities against the tested MTB H37Rv and MDR‐TB strains with minimum inhibitory concentration (MIC) in a range of 0.20 to 128 μg/mL. In particular, the most active hybrid 5e (MIC: 0.20 and 0.5 μg/mL) was four and two times more active than the parent ciprofloxacin (MIC: 0.78 μg/mL) and rifampicin (MIC: 0.39 μg/mL) against MTB H37Rv, and 4–>256 times more potent than the three references ciprofloxacin (MIC: 2.0 μg/mL), rifampicin (MIC: 32 μg/mL), and isoniazid (>128 μg/mL) against MDR‐TB. Thus, this kind of hybrids holds great promise as future anti‐TB agents against both drug‐sensitive and drug‐resistant MTB strains infection.     

Gatifloxacin–Isatin Hybrids and Their Antimycobacterial Activities

We report herein the design, synthesis, and antimycobacterial activity of a series of diethylene glycol tethered gatifloxacin–isatin hybrids 5a – o in this paper. Results revealed that all hybrids showed promising activity against both drug‐sensitive and multidrug‐resistant Mycobacterium tuberculosis strains with minimum inhibitory concentration (MIC) in a range of 1–128 μg/mL. Particularly, hybrid 5j with low cytotoxicity in VERO cell line was comparable with the parent gatifloxacin (MIC: 0.78 and 1 μg/mL) against MTB H37Rv and MDR‐TB strains, and ≥32‐fold more potent than isoniazid and rifampicin (MIC: >128 and 32 μg/mL, respectively) against MDR‐TB, suggesting it may serve as a new and promising candidate for further study.     

Design,Synthesis, and in vitro Antimycobacterial Activity of Propylene‐tethered Isatin Dimmers

A set of propylene‐tethered isatin dimmers 2a–i was synthesized via click chemistry and screened for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant TB. In spite of all dimmers (minimum inhibitory concentration: 25– > 128 μg/mL) only exhibited weak to moderate activities against the tested MTB H₃₇Rv and multidrug‐resistant TB, the structure–activity relationship was enriched and the results warrant further development of the anti‐TB properties of this kind of dimmers.     

Influence of Halogen Substitution in the Ligand Sphere on the Antitumor and Antibacterial Activity of Half‐sandwich Ruthenium(II) Complexes [RuX(η6‐arene)(C5H4N‐2‐CH=N‐Ar)]+

New complexes [(η⁶‐p‐cymene)Ru(C₅H₄N‐2‐CH=N–Ar)X]PF₆ [X = Br ( 1 ), I ( 2 ); Ar = 4‐fluorophenyl ( a ), 4‐chlorophenyl ( b ), 4‐bromophenyl ( c ), 4‐iodophenyl ( d ), 2,5‐dichlorophenyl ( e )] were prepared, as well as 3a – 3e (X = Cl) and the new complexes [(η⁶‐arene)RuCl(N‐N)]PF₆ (arene = C₆H₅OCH₂CH₂OH, N‐N = 2,2′‐bipyridine ( 4 ), 2,6‐(dimethylphenyl)‐pyridin‐2‐yl‐methylene amine ( 5 ), 2,6‐(diisopropylphenyl)‐pyridin‐2‐yl‐methylene amine ( 6 ); arene = p‐cymene, N‐N = 4‐(aminophenyl)‐pyridin‐2‐yl‐methylene amine ( 7 )]. X‐ray diffraction studies were performed for 1a , 1b , 1c , 1d , 2b , 5 , and 7 . Cytotoxicities of 1a – 1d and 2 were established versus human cancer cells epithelial colorectal adenocarcinoma (Caco‐2) (IC₅₀: 35.8–631.0 μM), breast adenocarcinoma (MCF7) (IC₅₀: 36.3–128.8.0 μM), and hepatocellular carcinoma (HepG2) (IC₅₀: 60.6–439.8 μM), 3a – 3e were tested against HepG2 and Caco‐2, and 4 – 7 were tested against Caco‐2. 1 – 7 were tested against non‐cancerous human epithelial kidney cells. 1 and 2 were more selective towards tumor cells than the anticancer drug 5‐fluorouracil (5‐FU), but 3a – 3e (X = Cl) were not selective. 1 and 2 had good activity against MCF7, some with lower IC₅₀ than 5‐FU. Complexes with X = Br or I had moderate activity against Caco‐2 and HepG2, but those with Cl were inactive. Antibacterial activities of 1a , 2b , 3a , and 7 were tested against antibacterial susceptible and resistant Gram‐negative and ‐positive bacteria. 1a , 2b , and 3a showed activity against methicillin‐resistant S. aureus (MIC = 31–2000 μg · mL^–1).     

Quinoline Derivatives with Potential Activity Against Multidrug‐resistant Tuberculosis

Tuberculosis (TB), which affects primarily the lungs (pulmonary TB) apart from other vital organs, is a life‐threatening chronic deadliest infectious disease caused by members of Mycobacterium tuberculosis (MTB) complex and mainly by MTB itself. The emergence of MTB new virulent forms that are resistant to some or all first‐line and second‐line anti‐TB agents, including multidrug‐resistant (MDR), extensively drug‐resistant, and totally drug‐resistant strains has further aggravated the spread of this disease and was increased up to an alarming level in the recent decades. More than ever, it is imperative to develop novel, high effective, and fast acting anti‐TB drugs to prevent the spread of TB, particularly in its hard‐to‐kill MDR‐TB, extensively drug‐resistant‐TB, and totally drug‐resistant‐TB strains. In recent years, numerous compounds have been synthesized for this purpose, but only a handful of compounds have entered human trials after the discovery of rifampicin, reflecting the inherent difficulties of developing new anti‐TB agents. Despite of bedaquiline and delamanid have received approval from many countries for treatment of MDR‐TB infected patients, both drugs are associated with serious side effects and are only recommended for those MDR‐TB patients without other treatment options. All these aforementioned facts make it an urgent need to develop novel drugs. Quinoline‐based derivatives including quinolones ex biological activities, and some of them displayed excellent in vitro and in vivo activities against MDR‐TB. This review outlines the recent developments of quinoline‐based derivatives with potential activity against MDR‐TB as well as the structure–activity relationship.     

Moxifloxacin/Gatifloxacin‐1,2,3‐triazole‐isatin Hybrids with Hydrogen‐Bond Donor and Their In Vitro Anticancer Activity

A series of novel moxifloxacin/gatifloxacin‐1,2,3‐triazole‐isatin hybrids ( 8a – i ) were designed, synthesized, and screened for their in vitro anticancer activity in this paper. All of the synthesized hybrids were active against A549 and HepG2 cancer cell lines, whereas the parent drugs moxifloxacin and gatifloxacin were devoid of activity. Among them, hybrid 8i (IC₅₀: 41.1–98.3 μM) showed considerable activity against A549, HepG2, and MCF‐7 cancer cell lines, and it was no inferior to Vorinostat (IC₅₀: 64.32 to >100 μM) against the three cancer cell lines. Thus, this kind of hybrids has potentiality for discovery of new anticancer candidates for clinical deployment in the control and eradication of cancers.     

Synthesis,Anticancer Evaluation,and Molecular Docking Studies of Novel (4‐Hydroxy‐2‐Thioxo‐3,4‐Dihydro‐2H‐[1,3]Thiazin‐6‐Yl)‐Chromen‐2‐Ones via a Multicomponent Approach

A series of coumarin‐substituted 1,3‐thiazine‐2‐thione derivatives ( 4a–m ) were synthesized via the multicomponent reaction of 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehyde ( 1 ) carbon disulfide ( 2 ), and various primary amines ( 3 ), in presence of triethylamine and acetonitrile under stirring with good yields. The structures of all the synthesized compounds were characterized by analytical and spectral studies. Further, the synthesized compounds were screened for their in vitro antiproliferative activities against different cancer cell lines (A549, MDA‐MB‐231, MCF7, HeLa, and B16F10). Studies on the molecular interactions to recognize the hypothetical binding motif of the title compounds with the target Hsp 100 were carried out employing the Schrodinger software. Compounds 4a , 4c and 4m showed activity against all the five cell lines compared with the reference drug, and 4a exhibited the least IC₅₀ concentration of 7.56 ± 1.07 μg/mL against MCF7. This in vitro anticancer result was supported by in silico docking and in silico ADME (absorption, distribution, metabolism, and excretion) studies as well.     

Heteronuclear 5‐Fluoroisatin Dimers: Design,Synthesis, and Evaluation of Their In Vitro Anti‐mycobacterial Activities

A series of novel heteronuclear 5‐fluoroisatin dimers 4a–j tethered through ethylene were designed, synthesized, and examined for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis H37Rv and multi‐drug resistant tuberculosis (MDR‐TB). All hybrids exhibited potential anti‐mycobacterial activities against the tested two strains with minimum inhibitory concentration (MIC) in a range of 25 to 256 μg/mL. In particular, the heteronuclear 5‐fluoroisatin dimer 4a (MIC: 25 and 32 μg/mL) was most active against Mycobacterium tuberculosis H37Rv and MDR‐TB strains, which was twofold and greater than fourfold more potent than rifampicin (MIC: 64 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR‐TB, warrant further optimization.     

Isatin‐(thio)semicarbazide/oxime‐1H‐1,2,3‐triazole‐coumarin Hybrids: Design,Synthesis, and in vitro Anti‐mycobacterial Evaluation

Isatin and coumarin derivatives with potential anti‐tubercular activity, while (thio)semicarbazide/oxime and 1H‐1,2,3‐triazole moieties exhibited favorable properties such as hydrogen bonding and/or metal chelation capability, so integration of the four pharmacophores into one molecule may provide more effective anti‐tubercular candidates. Based on the consideration earlier, 12 isatin‐(thio)semicarbazide/oxime‐1H‐1,2,3‐triazole‐coumarin hybrids 8a–l were designed, synthesized, and evaluated for their in vitro anti‐mycobacterial activities against M. tuberculosis (MTB) H₃₇Rv and MDR‐TB. The results showed that all the hybrids (MIC: 50–>200 μg/mL) exhibited weak to moderate inhibitory activity against MTB H₃₇Rv and MDR‐TB, which were far less potent than the references isoniazid (MIC: 0.05 μg/mL) and rifampicin (MIC: 0.39 μg/mL) against MTB H₃₇Rv. The most active hybrid 8h (MIC: 50 μg/mL) was comparable with rifampicin (MIC: 32 μg/mL) and more active than isoniazid (MIC: >128 μg/mL) against MDR‐TB, could be act as a lead for further optimization. Moreover, the enriched structure–activity relationship paved the way to the further rational development of this kind of hybrids.