Synthesis and biological evaluation of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione as antimycobacterial agents

Resistance among dormant mycobacteria leading to multidrug‐resistant and extremely drug‐resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione derivatives ( 4a–5c ) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC₅₀) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram‐negative and Gram‐positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 μg/ml against THP‐1, A549, and PANC‐1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection.     

Synthesis and Antitubercular Screening of [(2‐Chloroquinolin‐3‐yl)methyl] Thiocarbamide Derivatives

A series of 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]thiocarbamide and 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]methylthiocarbamide derivatives was synthesized as antitubercular agent. The structure of quinolinyl amines and their thiocarbamide derivatives were established on the basis of IR, ¹H and ¹³C‐NMR and mass spectral data. All the compounds were tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis (ATCC‐25177) in Lowenstein‐Jensen medium by well diffusion method and MIC by twofold serial dilution method. Results of the antitubercular screening revealed that compounds showed moderate to good antitubercular activity. Compound having two halogens in the phenyl rings viz. 3g , 3h , 4g, and 4h exhibited MIC of 50 μg/mL. The computational parameters relevant to absorption and permeation of target compounds were also calculated and found to be well correlated with antitubercular activity.     

Synthesis and Comparative Study of Anti‐Mycobacterium Activity of a Novel Series of Fluoronitrobenzothiazolopyrazoline Regioisomers

In an attempt to find a new and a safer drug for tuberculosis, we have synthesized a series of fluoronitrobenzothiazolopyrazolines for antitubercular activity. The series comprises three subclasses: fluorobenzothiazolopyrazolines ( 11a–f ), fluoronitrobenzothiazolopyrazoline, nitro group at 5^th position ( 12a–f ) and 4^th position ( 13a–f ). All compounds were screened for their in‐vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain by using Middlebrook 7H‐9 broth. An introduction of ? NO₂ group at 5^th position of benzothiazole ring ( 12a–f ) increased the antitubercular activity whereas introduction of ? NO₂ group at 4^th position ( 13a–f ) was found to decrease the activity remarkably. Two compounds from each series showing good antitubercular activity were tested for cytotoxicity on THP‐1 cell lines and they showed low cytotoxicity.     

Synthesis and In Vitro Antibacterial Activity of 7‐(3‐Alkoxyimino‐4‐methyl‐4‐methylaminopiperidin‐1‐yl)‐fluoroquinolone Derivatives

A series of novel 7‐(3‐alkoxyimino‐4‐methyl‐4‐methylaminopiperidin‐1‐yl)fluoroquinolone derivatives were designed, synthesized, and characterized by ¹H‐NMR, MS, and HRMS. These fluoroquinolones were evaluated for their in‐vitro antibacterial activity against representative Gram‐positive and Gram‐negative strains. Generally, all of the target compounds have considerable antibacterial activity against the tested forty strains, and exhibit exceptional potency in inhibiting the growth of methicillin‐sensitive Staphylococcus aureus (MSSA) and methicillin‐resistant S. aureus (MRSA) ATCC33591 (MICs: 0.06 to 2 μg/mL). In particular, compounds 14 , 19 , 28 , and 29 are fourfold more potent than ciprofloxacin against MSSA 08‐49. Compounds 23 , 26 , and 27 are twofold more potent than ciprofloxacin against MRSA ATCC33591 and MSSA ATCC29213. In addition, compound 14 exhibits excellent activity (MIC: 0.06 μg/mL) against Acinetobactes calcoaceticus, which is two‐ to 16‐fold more potent than the reference drugs gemifloxacin, levofloxacin, and ciprofloxacin.     

Synthesis and in‐vitro Antimycobacterial Evaluation of 1‐(Cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐ 8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids

Fifty one newer 1‐(cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids were synthesized from 1,3‐dichloro‐2‐methylbenzene and evaluated for in‐vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi‐drug resistant Mycobacterium tuberculosis (MDR‐TB), and Mycobacterium smegmatis (MC²). Among the synthesized compounds, 1‐cyclopropyl‐1,4‐dihydro‐7‐(3,4‐dihydro‐6,7‐dimethoxyisoquinolin‐2(1H)‐yl)‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9p was found to be the most active compound in vitro with a MIC value of 0.39 μM against MTB. Against MDR‐TB, compound 7‐(2‐carboxy‐5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl)‐1‐cyclopropyl‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9n was found to be the most active with a MIC value of 0.09 μM.     

Design,Synthesis, and Biological Evaluation of 1,4‐dihydropyridine Derivatives as Potent Antitubercular Agents

A series of novel 1,4‐dihydropyridine‐3,5‐dicarbamoyl derivatives bearing an imidazole nucleus at C‐4 position were synthesized in excellent yields via multicomponent Hantzsch reaction. The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectroscopy. The synthesized compounds 3a‐p were screened for antitubercular activity. Among all the screened compounds, compounds 3j and 3m showed most prominent activity against Mycobacterium tuberculosis with minimum inhibitory concentration of 0.02 μg/mL and SI > 500, making it more potent than first‐line antitubercular drug isoniazid. In addition, these compounds displayed relatively low cytotoxicity.     

Design,synthesis, and evaluation of new α‐aminonitrile‐based benzimidazole biomolecules as potent antimicrobial and antitubercular agents

The study explores the one‐pot synthesis of novel α‐aminonitriles by reacting 4‐[(1H‐benzimidazol‐2‐yl)methoxy]benzaldehyde, substituted anilines and sodium cyanide using a catalytic amount of copper dipyridine dichloride (CuPy₂Cl₂) and employing the Strecker reaction under mild conditions. All the synthesized compounds were screened for antimicrobial and antitubercular activity. The promising lead compounds 4d and 4e were identified, with MIC values ranging between 3.9 and 7.8 µg/mL against different bacterial strains. Compounds 4c–e and 4g also showed good antifungal activities against the tested fungal strain. Among those tested, compound 4e exhibited excellent antitubercular activity (MIC 0.05 μg/mL) with a low level of cytotoxicity, suggesting that compound 4e is a promising lead for subsequent investigations in search for new antitubercular agents.

     

Synthesis and Antibacterial Activity of a Novel Series of 2,3‐Diaryl‐substituted‐imidazo(2,1‐b)‐benzothiazole Derivatives

Benzothiazole and imidazole compounds are extensively studied heterocyclics due to their wide spectrum of bioactivities. Among them, the imidazo(2,1‐b)‐benzothiazole derivatives are pharmacologically important because of their immunostimulant, anti‐inflammatory, antifungal, antimicrobial, antitumor, and other activities. In the present research work, a novel series of 2,3‐diaryl‐substituted imidazo(2,1‐b)‐benzothiazoles 13a–o have been synthesized by reaction of substituted 2‐aminobenzothiazoles 1–8 and an appropriately substituted α‐bromo‐1‐(4′′‐substituted)‐phenyl‐2‐(4′‐substituted)‐phenyl‐1‐ethanones 9–12 in the presence of anhydrous acetonitrile. They were characterized by physicochemical, elemental, and spectral (IR, ¹H‐NMR, and Mass) data. All the synthesized compounds were screened for their in‐vitro antibacterial activity against Gram‐positive, Gram‐negative bacteria. The investigation of antibacterial screening data revealed that most of the compounds tested have demonstrated congruent activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa as compared with the standard ampicillin. Among the series, compounds 13d , 13h , and 13m exhibited excellent an antibacterial activity profile as compared with the standard. In summary, preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activities and they warrant more consideration as prospective antimicrobials.     

Synthesis and Antimicrobial Activity of 4‐Chloro‐3‐Nitrophenylthiourea Derivatives Targeting Bacterial Type II Topoisomerases

A series of novel 4‐chloro‐3‐nitrophenylthiourea derivatives were synthesized and evaluated for their antimicrobial, antibiofilm and tuberculostatic activities. Most of compounds exhibited high antibacterial activity against both standard and hospital strains (MIC values 0.5–2 μg/mL), as compared to Ciprofloxacin. Derivatives with 3,4‐dichlorophenyl ( 11 ) and 3‐chloro‐4‐methylphenyl ( 13 ) substituents were the most promising towards Gram‐positive pathogens. Both of them exhibited antibiofilm potency and effectively inhibited the formation of biofilms of methicillin‐resistant and standard strains of Staphylococcus epidermidis. Two N‐alkylthioureas ( 20, 21 ) showed twofold to fourfold increase in in vitro potency against isolates of Mycobacterium tuberculosis, as compared to Isoniazid. An action of 7, 10 , 11, 13, 20 and 21 against activity of topoisomerases isolated from Staphylococcus aureus was studied. Synthesized compounds were found as non‐genotoxic.     

Fungicide Activity of 5‐(4‐Chlorobenzylidene)‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐one against Cryptococcus Neoformans

The present work describes the synthesis and antifungal evaluation of new 5‐arylidene‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐ones 4a – f , obtained by the reaction of aromatic aldehydes 1 and rhodanine 2 followed by treatment with DMF. All compounds were tested against a panel of yeasts, hialohyphomycetes, and dermatophytes using the microbroth dilution method. Compounds 4a and 4c showed antifungal activity, with compound 4a being the most active one. Compound 4a demonstrated to be fungicidal rather than fungistatic and selective activity against Cryptococcus neoformans and dermatophytes. MIC₁₀₀, MIC₈₀, and MIC₅₀ of 4a were determined against a panel of clinical isolates of C. neoformans showing ranges of MICs between 2 and 16 μg/mL.     

Design,Synthesis, and in vitro antitubercular activity of 1,2,3‐triazolyl‐dihydroquinoline derivatives

In the quest for new active molecules against Mycobacterium tuberculosis, a series of dihydroquinoline derivatives possessing triazolo substituents were efficiently synthesized using click chemistry. The structure of 6l was evidenced by X‐ray crystallographic study. The newly synthesized compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The compounds 6a , 6g, and 6j (MIC: 3.13 μg/ml) showed promising activity when compared to the first‐line drug such as ethambutol. In addition, the structure and antitubercular activity relationship were further supported by in silico molecular docking studies of the active compounds against 3IVX.PDB (crystal structure of pantothenate synthetase in complex with 2‐(2‐(benzofuran‐2‐ylsulfonylcarbamoyl)‐5‐methoxy‐1H‐indol‐1‐yl)acetic acid).     

Design,synthesis, and in vitro antituberculosis activity of benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐oxadiazole derivatives

A new antitubercular agents, benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐ oxadiazole hybrids ( 6a–o ), have been designed and synthesized involving oxidative cyclization of hydrazones by use of di(acetoxy)iodobenzene, characterized by IR,¹H NMR,¹³C NMR, and HRMS, and further confirmed by X‐ray analysis. All the newly synthesized compounds 4a–o evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Among the compounds tested, the compounds 4o (MIC: 1.56  μg/ml) and 4l, 4m (MIC: 3.125  μg/ml) are promising lead analogues and have shown lower cytotoxicity.     

Exploration of 5‐(5‐nitrothiophen‐2‐yl)‐4,5‐dihydro‐1H‐pyrazoles as selective,multitargeted antimycobacterial agents

We report the biological evaluation of 5‐(5‐nitrothiophen‐2‐yl)‐4,5‐dihydro‐1H‐pyrazole derivatives against bacteria, eukaryotic cell lines and the assessment of their mechanisms of action to determine their prospects of being developed into potent antituberculosis agents. The compounds were evaluated for their antibacterial property against Mycobacterium tuberculosis H37Rv, multidrug‐resistant M. tuberculosis, Mycobacterium bovis BCG, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus using high‐throughput spot‐culture growth inhibition assay. They were found to be selective toward slow‐growing mycobacteria and Gram‐positive bacteria. In M. bovis BCG, they exhibited a bactericidal mode of action. Cytotoxicity was assessed in human THP‐1 and murine RAW 264.7 cell lines, and the compounds showed a lower cytotoxicity potential when compared with their antibacterial activity. They were found to be excellent whole‐cell efflux pump inhibitors of the mycobacterial surrogate M. aurum, performing better than known efflux pump inhibitor verapamil. The 5‐nitrothiophene moiety was identified for the first time as a prospective inhibitor scaffold of mycobacterial arylamine N‐acetyltransferase enzyme, which is the key enzyme in metabolizing isoniazid, a first‐line antituberculosis drug. The two aforementioned findings make the compounds potential hits in the development of adjunctive tuberculosis therapy.     

Antibacterial and antitubercular evaluation of dihydronaphthalenone‐indole hybrid analogs

A new series of indole appended dihydronaphthalenone hybrid analogs ( 5a–t ) have been synthesized through the Lewis acid catalyzed Michael addition of indoles to the arylidene/hetero arylidene ketones. All the synthesized derivatives are well characterized through the ¹H‐NMR, ¹³C‐NMR, HRMS spectroscopic techniques, compound 5r was further confirmed through single crystal X‐ray analysis and screened for antibacterial and antitubercular activities. Among the synthesized compounds, the minimum inhibition concentration of 5l (against Escherichia coli) and 5o & 5p (against E. coli & Staphylococcus aureus) was found to be as low as 3.12 μg/ml as compared to the standard antibacterial drug ciprofloxacin 2.5 μg/ml. In antitubercular activity, compounds 5o and 5p with minimum inhibition concentration 6.25 μg/ml were found to be comparable with that of the drugs Pyrazinamide 5 μg/ml and Streptomycin 5 μg/ml. Compounds 5i , 5j , 5m , 5n , 5q , and 5r also showed promising activity against group of organisms tested.     

Synthesis and In‐Vitro Antitumor Activities of Some Mannich Bases of 9‐Alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones

A novel series of 2‐substituted aminomethyl‐9‐alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones 5a – q was synthesized via aminomethylation of 9‐alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones 4a – e with hydrochlorides of the respective amines 6a – m . The structures of these newly synthesized compounds were characterized by ¹H‐NMR, MS, and elemental analysis. All the compounds were tested for their cytotoxic activity in vitro against four human tumor cell lines including human non‐small lung cancer cells (A549), human gastric adenocarcinoma (SGC), human colon cancer cell (HCT116), human myeoloid leukemia cells (K562), and one multi‐drug resistant subline (KB‐VCR). Most compounds showed moderate to potent cytotoxic activity against the tested cell lines. Preliminary mechanism research indicated that the most promising compound, 2‐diethylaminomethyl‐9‐methyl‐1,2,3,4‐tetrahydrocarbazole‐1‐one 5c , exhibited a potential inhibitory effect against microtubule.     

Synthesis and in‐vitro Cytotoxicity of Poly‐functionalized 4‐(2‐Arylthiazol‐4‐yl)‐4H‐chromenes

A new series of 4‐aryl‐4H‐chromenes bearing a 2‐arylthiazol‐4‐yl moiety at the 4‐position were prepared as potential cytotoxic agents. The in‐vitro cytotoxic activity of the synthesized 4‐aryl‐4H‐chromenes was investigated in comparison with etoposide, a well‐known anticancer drug, using MTT colorimetric assay. Among them, the 2‐(2‐chlorophenyl)thiazol‐4‐yl analog 4b showed the most potent activity against nasopharyngeal epidermoid carcinoma KB, medulloblastoma DAOY, and astrocytoma 1321N1, and compound 4d bearing a 2‐(4‐chlorophenyl)thiazol‐4‐yl moiety at the 4‐position of the chromene ring exhibited the best inhibitory activity against breast cancer cells MCF‐7, lung cancer cells A549, and colon adenocarcinoma cells SW480 with IC₅₀ values less than 5 μM. The ability of compound 4b to induce apoptosis was confirmed in a nuclear morphological assay by DAPI staining in the KB and MCF‐7 cells.     

6‐Hydrogen‐8‐Methylquinolones Active Against Replicating and Non‐replicating Mycobacterium tuberculosis

The screening of an in‐house quinolones library against Mycobacterium tuberculosis (Mtb) H₃₇Rv, followed by a first cycle of optimization, yielded 6‐hydrogen‐8‐methyl derivatives endowed with good potency. The antitubercular activity also encompassed the bacteria in a non‐replicating state (NRP‐TB) with minimum inhibitory concentration values lower than those of the reference agent, moxifloxacin. Among the best compounds, 11w and 11ai , characterized by a properly substituted piperidine at the C‐7 position, were active against single‐drug‐resistant (SDR‐TB) Mtb strains, maintaining overall good potency also against ciprofloxacin‐resistant Mtb. This study expands the body of SAR around antitubercular quinolones leading to reconsider the role played by the usual fluorine atom at the C‐6 position. Further elaboration of the 6‐hydrogen‐8‐methylquinolone scaffold, with a particular focus on the C‐7 position, is expected to give even more potent congeners holding promise for shortening the current anti‐TB regimen.     

Synthesis and Anticonvulsant Activity of New N‐(Alkyl/Sub‐stituted aryl)‐N′‐[4‐(5‐cyclohexylamino)‐1,3,4‐thiadiazole‐2‐yl)phenyl]thioureas

A series of novel thiourea derivatives carrying the 5‐cylohexylamino‐1,3,4‐thiadiazole moiety was synthesized and their anticonvulsant activity was evaluated. Structures of the synthesized compounds have been confirmed by IR, ¹H‐NMR, and elemental analysis. All of the compounds were administered at a dose of 50 mg/kg. Some of the active compounds have different effects in pentylenetetrazole (PTZ) and maximal electroshock (MES) tests, indicating the therapeutical potential in petit mal seizures, but not in grand mal seizures. Compounds 10 , 11 , 13 , and 14 carrying 2‐methylphenyl, 4‐chlorophenyl, allyl, and 4‐methylphenyl on the thiourea pharmacophore, increased the survival rate in the PTZ model. The ED₅₀ values of the active compounds 10 , 11 , 13 , and 14 were found 68.42, 43.75, 18.75 and 25 mg/kg, respectively.     

Synthesis,molecular modeling,in vivo study,and anticancer activity of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen

A new series of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen ( 7a–m ) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier‐transform infrared spectroscopy, ¹H‐nuclear magnetic resonance (NMR), ¹³C‐NMR, and high‐resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase‐2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU‐145, and LNCaP) using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU‐145 and LNCaP cancer cell lines with IC₅₀ values of 26.0, 34.5, and 48.8 μM, respectively. Compounds 7b , 7k , and 7m showed anticancer activity against cancer cell lines PC3 and DU‐145 with IC₅₀ values of 43.0, 36.5, 29.3 μM and 49.8, 49.1, 31.6 μM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC₅₀ values of 43.4 and 34.5 μM, respectively. To assess the biodistribution in mice of IRDye800, dye‐labeled compound 7a or 100 μM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.