1H‐1,2,3‐triazole‐tethered 8‐OMe Ciprofloxacin and Isatin Hybrids: Design,Synthesis and in vitro Anti‐mycobacterial Activities

A new class of 1H ‐1,2,3‐triazole‐tethered 8‐OMe ciprofloxacin (8‐OMe CPFX) isatin hybrids 5a–l was designed, synthesized and screened for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis H₃₇Rv and multi‐drug‐resistant tuberculosis (MDR‐TB). All targets (minimum inhibitory concentration (MIC): 0.20–8.0 μg/mL) exhibited promising inhibitory activity against MTB H₃₇Rv and MDR‐TB. Among them, conjugate 5h (MIC: 0.20 μg/mL), was 2–16 times more potent in vitro than the references CPFX (MIC: 3.12 μg/mL), 8‐OMe CPFX (MIC: 1.56 μg/mL) and RIF (MIC: 0.39 μg/mL) against MTB H₃₇Rv. The most potent hybrid 5l (MIC: 0.25 μg/mL) was 8–256 times more active than the three references (MIC: 2.0–64 μg/mL) against MDR‐TB. Both of them warrant further investigations.     

Synthesis of novel 2,3‐disubstituted quinazolin‐4(3H)‐one derivatives containing hydrazone skeleton as potent urease inhibitors and their antimicrobial activities

A new series of quinazolinones containing hydrazone moiety were synthesized, and their inhibitory activities on urease were assessed in vitro. Most of the compounds exhibited potent urease inhibitory activity. Among the synthesized compounds, molecule 4a bearing furan ring has the best inhibitory effect against urease with IC₅₀ = 2.90 ± 0.11 μg/mL. Compounds 4f , 4g , 4h , 4i , and 4j have hydroxy group on phenyl ring. Compound 4i is the most active inhibitor among these compounds with IC₅₀ = 5.01 ± 0.10 μg/mL, which has 3‐Cl and 4‐Br on phenyl ring. Also, newly synthesized compounds had been tested for their antimicrobial effects against three of Gram‐positive bacteria (Bacillus cereus 702 Roma, Staphylococcus aureus ATCC 25923, and Streptococcus pyogenes ATCC 19615) and three of Gram‐negative bacteria (Escherichia coli ATCC 25922, Proteus vulgaris ATCC 13315, and Pseudomonas aeruginosa ATCC 27853). Antimicrobial activity results show that compounds 4a , 4h , 4j , 4f , and 4l have the lowest minimum inhibitory concentration (MIC) value of 1000 μg/mL to all tested bacteria. The other compounds have the MIC value of >1000 μg/mL to all tested bacteria.     

Novel Pyrazoline‐based Organometallic Compounds Containing Ferrocenyl and Quinoline units: Synthesis,Characterization and Microbial susceptibilities

Some novel pyrazoline‐based organometallic compounds were synthesized as new leads in antimicrobial chemotherapy. The structures of compounds were elucidated by different spectroscopic techniques and elemental analyses. All compounds were investigated for in vitro antimicrobial studies against fifteen ATTC bacterial and fungal strains. The microbial susceptibility of these compounds revealed that all the tested compounds gave good minimum inhibitory concentration (MIC) values against the tested organisms that are either similar or even better than the reference drugs amoxicillin and fluconazole, which gave MIC values 8‐64 μg/ml against bacterial and 64 μg/ml against fungal strains, respectively. Among all compounds, compound ( 4d ) 1‐(5‐(4‐chlorophenyl)‐3‐ferrocenyl‐4,5‐dihydropyrazol‐1‐yl)‐2‐quinolin‐8‐yloxy) ethanone, emerged out the most promising antimicrobial organometallic derivative with MIC values against all the strains ranging from 8‐32 μg/ml. Other compounds gave a range of MIC values between 16‐64 μg/ml against S. bovis, 16‐32 μg/ml against E. coli, and C. tropicalis except compound ( 4d) which gave MIC 8 μg/ml against S. bovis and E. coli, whereas 32 μg/ml against C. tropicalis. Collectively, these compounds gave a lower MIC value between 32‐64 μg/ml against both of the biofilm forming strains namely, P. aeruginosa and S. mutans. The results of microbial susceptibility concluded that these novel organometallic compounds are new leads in antimicrobial chemotherapy and can be very useful for further optimization work on microbial chemotherapy.     

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.     

Design,Synthesis, and Antimycobacterial Activities of Diethylene Glycol Tethered Moxifloxacin–Isatin Hybrids

A new class of diethylene glycol tethered moxifloxacin–isatin hybrids 5a–l was designed, synthesized, and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis (MTB) H37Rv and multidrug‐resistant tuberculosis (MDR‐TB) strains. Our results showed that all hybrids with higher lipophilicity than the parent moxifloxacin exhibited promising activity against the tested strains with minimum inhibitory concentration (MIC) in a range of 0.2–16 μg/mL. In particular, hybrid 5h (MIC: 0.20 and 0.5 μg/mL), which was found to be most active against MTB H37Rv and MDR‐TB, was twofold more potent than isoniazid (MIC: 0.39 μg/mL) against MTB H37Rv and ≥64‐fold more active than isoniazid and rifampicin (MIC: >128 and 32 μg/mL, respectively) against MDR‐TB.     

Ciprofloxacin‐isatin‐1H‐1,2,3‐triazole Hybrids: Design,Synthesis, and in vitro Anti‐tubercular Activity against M. tuberculosis

A new set of ciprofloxacin (CPFX)‐isatin‐1H‐1,2,3‐triazole hybrids 6a – l with greater lipophilicity compared with the parent CPFX was designed, synthesized, and assessed for their in vitro anti‐mycobacterial activity against Mycobacterium tuberculosis (MTB) H₃₇Rv as well as cytotoxicity in VERO cell line. The preliminary results showed that all hybrids (MIC: 0.39–50 μg/mL) exhibited promising activities against MTB H₃₇Rv, and six of them (MIC: 0.39–1.56 μg/mL) were more active than the parent CPFX (MIC: 3.12 μg/mL). In particular, the most active conjugate 6h (MIC: 0.39 μg/mL) was comparable with RIF (MIC: 0.39 μg/mL), and eight times more potent than CPFX. All conjugates (CC₅₀: 4–64 μg/mL) were more toxic than the parent (CC₅₀: 128 μg/mL) in VERO cell lines, and the most active hybrids, which also displayed the highest cytotoxicity, should be further optimized.     

Efficient Synthesis of Novel 3‐Phenyl‐5‐thioxo‐3,4,5,6‐tetrahydroimidazo[4,5‐c]pyrazole‐2(1H)‐carbothioamide Derivatives Using a CeO2–MgO Catalyst and Evaluation of Antimicrobial Activity

Imidazo[4,5‐c ]pyrazole derivatives ( 3a–f , 4a–f , and 5a–f ) were efficiently synthesized by one‐pot three‐component reactions using CeO₂–MgO as the catalyst. The synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectroscopic analyses. The in vitro antimicrobial activity of the synthesized compounds against various bacterial and fungal strains was screened. Compound 3b was highly active [minimum inhibitory concentration (MIC): 0.5 μg/mL] against Gram‐positive Staphylococcus aureus , and compounds 3b , 3f , 4d , and 4e were highly active (MIC: 0.5, 2, 2, and 0.5 μg/mL, respectively) against Gram‐negative Pseudomonas aeruginosa and Klebsiella pneumoniae , relative to standard ciprofloxacin in the antibacterial activity screening. Compounds 3b and 4f were highly active (MIC: 4 and 0.5 μg/mL, respectively) against Aspergillus fumigatus and Microsporum audouinii in the antifungal activity screening compared with the clotrimazole standard.     

Tetraethylene Glycol Tethered Heteronuclear Bis‐isatin Derivatives: Design,Synthesis, and In Vitro Anti‐mycobacterial Activities

A series of novel tetraethylene glycol tethered heteronuclear bis‐isatin derivatives 7a – l were designed, synthesized, and evaluated for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis (MTB) H37Rv and multidrug‐resistant TB (MDR‐TB) as well as cytotoxicity in VERO cell line. All hybrids exhibited potential anti‐mycobacterial activities against MTB H37Rv and MDR‐TB, and acceptable cytotoxicity. Among them, the heteronuclear bis‐isatin 7l [minimum inhibitory concentration (MIC): 16 and 16 μg/mL] was found to be most active against MTB H37Rv and MDR‐TB strains, which was 2‐fold and >8‐fold, respectively, more potent than were the first‐line anti‐tubercular agents rifampicin (MIC: 32 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR‐TB, also demonstrated acceptable cytotoxicity profile (CC₅₀: 62.5 μg/mL), could act as a starting point for further optimization.     

Design,Synthesis, and In Vitro Anti‐mycobacterial Evaluation 1H‐1,2,3‐triazole‐tethered Ciprofloxacin and Isatin Conjugates

Eight novel 1H‐1,2,3‐triazole‐tethered ciprofloxacin (CPFX) isatin conjugates 5a – h with greater lipophilicity compared with CPFX were designed, synthesized, and evaluated for their in vitro anti‐mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis (MTB) H₃₇Rv. The preliminary results showed that all hybrids (MIC: 12.5–100 μg/mL) exhibited considerable activity against M. smegmatis , but less active than the parent CPFX (MIC: 6.25 μg/mL) and the reference INH (MIC: 0.78 μg/mL). Against MTB H₃₇Rv, all hybrids displayed excellent inhibitory activity with MICs ranging from 1.56 to 25 μg/mL, particularly, 5h (MIC: 1.56 μg/mL) was twofold more active CPFX (MIC: 3.12 μg/mL), warrant further investigations.     

Design,Synthesis, and in vitro Anti‐mycobacterial Evaluation of Propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered (Thio)semicarbazone‐isatin‐moxifloxacin Hybrids

A new class of propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered (thio)semicarbazone‐isatin‐moxifloxacin hybrids 6a – h was designed, synthesized, and screened for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis (MTB) H₃₇Rv and MDR‐TB as well as cytotoxicity in VERO cell line. All the synthesized hybrids (MIC: 0.05–2.0 μg/mL) exhibited excellent activities against M. tuberculosis H₃₇Rv and MDR‐TB; in particular, conjugate 6c (MIC: 0.05 and 0.12 μg/mL) was no inferior to the three references MXFX (MIC: 0.10 and 0.12 μg/mL), RIF (MIC: 0.39 and 32 μg/mL), and INH (MIC: 0.05 and >128 μg/mL) against the tested two strains. All hybrids (CC₅₀: 2–8 μg/mL) were much more cytotoxic than the parent MXFX (CC₅₀: 128 μg/mL) should be further optimized.     

Design,Synthesis and In Vitro Anti‐mycobacterial Activities of 8‐OMe Ciprofloxacin‐1H‐1,2,3‐triazole‐isatin‐(thio) Semicarbazide/Oxime Hybrids

A series of novel 8‐OMe ciprofloxacin (8‐OMe CPFX)‐1H‐1,2,3‐triazole‐isatin‐(thio) semicarbazide/oxime hybrids 6a – l with the capacity to form hydrogen bond were designed, synthesized, and evaluated for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis (MTB) H₃₇Rv and MDR‐TB as well as cytotoxicity. All the synthesized hybrids (MIC: 0.39–16 μg/mL) exhibited excellent activities against MTB H₃₇Rv and MDR‐TB, and the majority of them were more potent than the parent 8‐OMe CPFX (MIC: 1.56 and 2.0 μg/mL, respectively). In particular, the most active conjugate 6h (MIC: 0.39 and 1.0 μg/mL, respectively) was two to eight times more potent in vitro than the references CPFX (MIC: 3.12 and 4.0 μg/mL, respectively) and 8‐OMe CPFX against the tested strains and was comparable with or 64‐folds more potent than RIF (MIC: 0.39 and 64 μg/mL, respectively) against MTB H₃₇Rv and MDR‐TB, respectively. In addition, all conjugates (CC₅₀: 16–64 μg/mL) showed acceptable cytotoxicity, although most of them were more toxic than the parent (CC₅₀: 64 μg/mL) in VERO cell line.     

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

A series of propylene‐tethered mono‐/bis‐isatin‐gatifloxacin hybrids 3a–f and 4a–f were designed, synthesized, and evaluated for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis (MTB) H37Rv and multidrug‐resistant tuberculosis (MDR‐TB) as well as cytotoxicity against VERO cell line. The results indicated that all hybrids exhibited promising anti‐mycobacterial activities against MTB H37Rv and MDR‐TB with MIC ranging from 0.25 to 16 μg/mL. In particular, the mono‐isatin‐gatifloxacin hybrid 3e (MIC: 0.25 and 0.25 μg/mL) was found to be most active against MTB H₃₇Rv and MDR‐TB strains, which was twofold more active than the parent gatifloxacin (MIC: 0.5 μg/mL) and comparable with rifampicin ( RIF ) (MIC: 0.25 μg/mL) against MTB H₃₇Rv, and 4‐ > 512 times more potent than the three references gatifloxacin (MIC: 1.0 μg/mL), RIF (MIC: 64 μg/mL), and isoniazid (>128 μg/mL) against MDR‐TB, could act as a starting point for further optimization.     

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.     

Design,synthesis, and insecticidal activity of novel isoxazole derivatives containing bisamide moiety

In this study, a total of 31 novel isoxazole derivatives containing bisamide moiety were synthesized and evaluated for their insecticidal activity against Plutella xylostella (P. xylostella). Bioassays indicated that some of the target compounds exhibited good insecticidal activity against P. xylostella. In particular, compound E26 revealed excellent insecticidal activity against P. xylostella, with a 50% lethal concentration (LC₅₀) value of 4.6 μg/mL, which was even better than those of chlorpyrifos (7.7 μg/mL), beta‐cypermethrin (12.8 μg/mL), and azadirachtin (10.2 μg/mL). These results indicated that isoxazole derivatives containing bisamide moiety could be developed as novel and promising insecticides. To the best of our knowledge, it is the first report on the insecticidal activity of this series of novel isoxazole derivatives containing bisamide moiety.     

Design,Synthesis and In Vitro Anti‐mycobacterial Activity of Propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered Isatin‐moxifloxacin Hybrids

Ten propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered isatin‐moxifloxacin hybrids 5a–j were synthesized via Cu‐promoted azide‐alkyne cycloaddition reaction, and screened for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis H₃₇Rv and multidrug‐resistant tuberculosis. The results showed that all the synthesized hybrids [minimum inhibitory concentration (MIC): 0.25–4.0 μg/mL] displayed considerable activities against the tested two strains, but all less active than the parent moxifloxacin (MIC: 0.10 and 0.12 μg/mL). The resistance index of the most targets was around 1, suggesting this kind of hybrids could reduce the cross–resistance to some extent. Among them, hybrid 5 g was found most active against Mycobacterium tuberculosis H₃₇Rv with MIC of 0.39 μg/mL, which was comparable with rifampicin (MIC: 0.39 μg/mL), while conjugate 5a (MIC: 0.25 μg/mL) was 128– > 512 times more active than rifampicin (MIC: 32 μg/mL) and isoniazid (MIC: >128 μg/mL) against multidrug‐resistant tuberculosis.     

Synthesis,Characterization, and Antimicrobial Screening of 4″‐methyl‐2,2″‐diaryl‐4,2′:4′,5″‐terthiazole Derivatives

A series of novel 4″‐methyl‐2,2″‐diaryl‐4,2′:4′,5″‐terthiazole ( 8a‐p ) derivatives has been synthesized and screened for antibacterial activity against four pathogenic bacteria, Escherichia coli, Pseudomonas flurescence, Staphylococcus aureus, and Bacillus subtilis. Among them, compounds 8a and 8j exhibited excellent antibacterial activity with minimum inhibitory concentration range of 1.0 to 5.3 μg/mL and compounds 8m and 8p exhibited moderate to good antibacterial activity with minimum inhibitory concentration range of 16.9 to 29.7 μg/mL against all tested strains. All the synthesized compounds were screened for their in vitro antifungal activity against Cocinida candida. Most of the compounds reported moderate antifungal activity. This study provides valuable directions to our ongoing endeavor of rationally designing more potent antimicrobial agent.     

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.     

Design,Synthesis and in vitro Antimycobacterial Activities of Isatin‐1,2,3‐triazole‐moxifloxacin Hybrids

A new class of isatin‐1,2,3‐triazole‐moxifloxacin ( MXFX ) hybrids 5a–j was designed, synthesized, and screened for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H₃₇Rv and MDR‐TB. All the synthesized hybrids (MIC: 0.10–0.78 μg/mL) exhibited excellent activities against MTB H₃₇Rv and MDR‐TB, in spite of none of them were more potent than the parent MXFX (MIC: 0.10 and 0.12 μg/mL). Against MTB H₃₇Rv, the most active 5f (MIC: 0.10 μg/mL) was comparable with MXFX and 4 times more potent than RIF (MIC: 0.39 μg/mL). Against MDR‐TB, all hybrids were more active than RIF (MIC: 32 μg/mL) and INH (MIC: >128 μg/mL). In particular, hybrid 5e (MIC: 0.10 μg/mL) was comparable with MXFX and 256 and >1,024 times more potent than RIF and INH . Both conjugates 5e and 5f warrant further investigations.     

Microwave‐Assisted Synthesis and Antituberculosis Screening of Some 4‐((3‐(Trifluoromethyl)‐5,6‐dihydro‐[1,2,4]triazolo[4,3‐a]pyrazin‐7(8H)‐l)methyl)benzenamine Hybrids

In the present investigation, a series of 4‐((3‐(trifluoromethyl)‐5,6‐dihydro‐[1,2,4]triazolo[4,3‐a]pyrazin‐7(8H)‐yl)methyl)benzenamine analogs 6a–o were synthesized and characterized by IR, NMR (¹H and ¹³C), and mass spectra. All newly synthesized compounds 6a–o were prepared under conventional and microwave irradiation methods. These compounds obtained in higher yields and in shorter reaction times in the microwave irradiation method when compared with the conventional method. Synthesized compounds 6a–o were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇Ra using an established XTT reduction menadione assay. Among the screened compounds, 6i (IC₅₀: 1.82 μg/mL), 6j (IC₅₀: 1.02 μg/mL), and 6k (IC₅₀: 1.59 μg/mL) showed excellent activity. Furthermore, compound 6i showed MIC₉₀ value of 16.02 μg/mL. In summary, the results indicate the identification of some novel, selective, and specific inhibitors against M. tuberculosis that can be explored further for the potential antitubercular drug.     

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.