Design and Synthesis of the Linezolid Bioisosteres to Resolve the Serotonergic Toxicity Associated with Linezolid.

Serotonergic toxicity due to MAO enzyme inhibition is a significant concern when using linezolid to treat MDR-TB. To address this issue, we designed linezolid bioisosteres with a modified acetamidomethyl side chain at the C-5 position of the oxazolidine ring to balance activity and reduce toxicity. Among these bioisosteres, R7 emerged as a promising candidate, demonstrating greater effectiveness against M. tuberculosis (Mtb) H37Rv cells with an MIC of 2.01 µM compared to linezolid (MIC = 2.31 µM). Bioisostere R7 also exhibited remarkable activity (MIC50) against drug-resistant Mtb clinical isolates, with values of 0.14 µM (INHR, inhA+), 0.53 µM (INHR, katG+), 0.24 µM (RIFR, rpoB+), and 0.92 µM (INHR INHR, MDR). Importantly, it was >6.52 times less toxic as compared to the linezolid toward the MAO-A and >64 times toward the MAO-B enzyme, signifying a substantial improvement in its drug safety profile.

A Green one-pot three component synthesis of thiazolidine-2,4-dione based bisspirooxindolo-pyrrolidines with [Bmim]BF4: their in vitro and in silico anti-TB studies.

A simple and effective three-component one-pot green methodology was employed for the synthesis of a new thiazolidine-2,4-dione based bisspirooxindolo-pyrrolidine derivatives using [Bmim]BF4 ionic liquid via [3 + 2] cycloaddition reaction. It is an environmentally benign, column chromatography-free, shorter reaction time, good yield and easy product isolation method. The synthesized compounds 10a-x, were thoroughly characterized by using various spectroscopic methods like FT-IR, 1H NMR, 13C NMR, Mass spectrometry and finally by single crystal X-ray diffraction method. In vitro anti-tubercular (anti-TB) activity studies were carried out on these synthesized compounds, and they showed good to moderate anti-TB activity against Mycobacterium tuberculosis H37Rv strain. The compound 10a exhibited good anti-TB activity, with an MIC (Minimum Inhibitory Concentration) value of 12.5 µg/mL, and the compounds 10m, 10o and 10r showed moderate activity with an MIC value of 25.0 µg/mL. Remaining compounds exhibited poor activity against Mycobacterium tuberculosis. Ethambutol, rifampicin and isoniazid were used as standard drugs. Furthermore, in silico molecular docking experiments on the TB protein (PDB ID: 1DF7) were carried out to understand the binding interactions, and they showed least binding energy values ranging from -8.9 to -7.2 kcal/mol.

Discovery of potent antimycobacterial agents targeting lumazine synthase (RibH) of Mycobacterium tuberculosis.

Tuberculosis (TB) continues to be a global health crisis, necessitating urgent interventions to address drug resistance and improve treatment efficacy. In this study, we validate lumazine synthase (RibH), a vital enzyme in the riboflavin biosynthetic pathway, as a potential drug target against Mycobacterium tuberculosis (M. tb) using a CRISPRi-based conditional gene knockdown strategy. We employ a high-throughput molecular docking approach to screen ~ 600,000 compounds targeting RibH. Through in vitro screening of 55 shortlisted compounds, we discover 3 compounds that exhibit potent antimycobacterial activity. These compounds also reduce intracellular burden of M. tb during macrophage infection and prevent the resuscitation of the nutrient-starved persister bacteria. Moreover, these three compounds enhance the bactericidal effect of first-line anti-TB drugs, isoniazid and rifampicin. Corroborating with the in silico predicted high docking scores along with favourable ADME and toxicity profiles, all three compounds demonstrate binding affinity towards purified lumazine synthase enzyme in vitro, in addition these compounds exhibit riboflavin displacement in an in vitro assay with purified lumazine synthase indicative of specificity of these compounds to the active site. Further, treatment of M. tb with these compounds indicate reduced production of flavin adenine dinucleotide (FAD), the ultimate end product of the riboflavin biosynthetic pathway suggesting the action of these drugs on riboflavin biosynthesis. These compounds also show acceptable safety profile in mammalian cells, with a high selective index. Hence, our study validates RibH as an important drug target against M. tb and identifies potent antimycobacterial agents.

Design, synthesis and molecular docking study of novel triazole-quinazolinone hybrids as antimalarial and antitubercular agents.

In a quest to discover new antimalarial and antitubercular drugs, we have designed and synthesized a series of novel triazole-quinazolinone hybrids. The in vitro screening of the triazole-quinazolinone hybrid entities against the plasmodium species P. falciparum offered potent antimalarial molecules 6c, 6d, 6f, 6g, 6j & 6k owing comparable activity to the reference drugs. Furthermore, the target compounds were evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv strain. Among the screened compounds, 6c, 6d and 6l were found to be the most active molecules with a MIC values of 19.57-40.68 µM. The cytotoxicity of the most active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed. The computational study including drug likeness and ADMET profiling, DFT, and molecular docking study was done to explore the features of target molecules. The compounds 6a, 6g, and 6k exhibited highest binding affinity of -10.3 kcal/mol with docked molecular targets from M. tuberculosis. Molecular docking study indicates that all the molecules are binding to the falcipain 2 protease (PDB: 6SSZ) of the P. falciparum. Our findings indicated that these new triazole-quinazolinone hybrids may be considered hit molecules for further optimization studies.

Thiazolotriazoles As Anti-infectives: Design, Synthesis, Biological Evaluation and In Silico Studies.

The rational design of novel thiazolo[2,3-c][1,2,4]triazole derivatives was carried out based on previously identified antitubercular hit molecule H127 for discovering potent compounds showing antimicrobial activity. The designed compounds were screened for their binding efficacies against the antibacterial drug target enoyl-[acyl-carrier-protein] reductase, followed by prediction of drug-likeness and ADME properties. The designed analogues were chemically synthesized, characterized by spectroscopic techniques, followed by evaluation of antimicrobial activity against bacterial and fungal strains, as well as antitubercular activity against M. tuberculosis and M. bovis strains. Among the synthesized compounds, five compounds, 10, 11, 35, 37 and 38, revealed antimicrobial activity, albeit with differential potency against various microbial strains. Compounds 10 and 37 were the most active against S. mutans (MIC: 8 µg/mL), while compounds 11 and 37 showed the highest activity against B. subtillis (MIC: 16 µg/mL), whereas compounds 10, 11 and 37 displayed activities against E. coli (MIC: 16 µg/mL). Meanwhile, compounds 10 and 35 depicted activities against S. typhi (MIC: 16 µg/mL) and compound 10 showed antifungal activity against C. albicans (MIC: 32 µg/mL). The current study has identified two broad-spectrum antibacterial hit compounds (10 and 37). Further structural investigation on these molecules is underway to enhance their potency.

In silico design, synthesis and antitubercular activity of novel 2-acylhydrazono-5-arylmethylene-4-thiazolidinones as enoyl-acyl carrier protein reductase inhibitors.

Mycobacteria regulate the synthesis of mycolic acid through the fatty acid synthase system type 1 (FAS I) and the fatty acid synthase system type-2 (FAS-II). Because mammalian cells exclusively utilize the FAS-I enzyme system for fatty acid production, targeting the FAS-II enzyme system could serve as a specific approach for developing selective antimycobacterial drugs. Enoyl-acyl carrier protein reductase enzyme (MtInhA), part of the FAS-II enzyme system, contains the NADH cofactor in its active site and reduces the intermediate. Molecular docking studies were performed on an in-house database (∼2200 compounds). For this study, five different crystal structures of MtInhA (PDB Code: 4TZK, 4BQP, 4D0S, 4BGE, 4BII) were used due to rotamer difference, mutation and the presence of cofactors. Molecular dynamics simulations (250 ns) were performed for the novel 2-acylhydrazono-5-arylmethylene-4-thiazolidinones derivatives selected by molecular docking studies. Twenty-three compounds selected by in silico methods were synthesized. Antitubercular activity and MtInhA enzyme inhibition studies were performed for compounds whose structures were elucidated by IR,1H-NMR,13C-NMR, HSQC, HMBC, MS and elemental analysis.Communicated by Ramaswamy H. Sarma.

N-Substituted piperazine-coupled imidazo[2,1-b]thiazoles as inhibitors of Mycobacterium tuberculosis: Synthesis, evaluation, and docking studies.

An innovative series of N-substituted piperazine-linked imidazothiazole derivatives 7(a-x) were synthesized, and their antitubercular effectiveness was evaluated. A three-step reaction sequence involving the condensation of 1,3-dichloroacetone and thiourea, coupling with substituted piperazines to give the intermediates 5(a-d) and cyclization with substituted α-bromoacetophenones produced the desired imidazothiazole derivatives 7(a-x) in excellent yields. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv resulted in 7k (minimum inhibitory concentration [MIC]: 0.78 µg/mL) and 7g and 7h (MIC: 1.56 µg/mL) as potent hit compounds. Further, the docking studies of the promising compounds 7k, 7g, and 7h revealed that the best molecular interactions are with the DprE1 in complex with sulfonyl PBTZ of M. tuberculosis as the target protein (PDB ID: 6G83).

Design, synthesis, anti-mycobacterial activity, molecular docking and ADME analysis of spiroquinoxaline-1,2,4-oxadiazoles via [3 + 2] cycloaddition reaction under ultrasound irradiation.

The development of anti-tuberculosis (anti-TB) drugs has become a challenging task in medicinal chemistry. This is because Mycobacterium tuberculosis (TB), the pathogen that causes tuberculosis, has an increasing number of drug-resistant strains, and existing medication therapies are not very effective. This resistance significantly demands new anti-TB drug profiles. Here, we present the design and synthesis of a number of hybrid compounds with previously known anti-mycobacterial moieties attached to quinoxaline, quinoline, tetrazole, and 1,2,4-oxadiazole scaffolds. A convenient ultrasound methodology was employed to attain spiroquinoxaline-1,2,4-oxadiazoles via [3 + 2] cycloaddition of quinoxaline Schiff bases and aryl nitrile oxides at room temperature. This approach avoids standard heating and column chromatography while producing high yields and shorter reaction times. The target compounds 3a-p were well-characterized, and their in vitro anti-mycobacterial activity (anti-TB) was evaluated. Among the screened compounds, 3i displayed promising activity against the Mycobacterium tuberculosis cell line H37Rv, with an MIC99 value of 0.78 µg/mL. However, three compounds (3f, 3h, and 3o) exhibited potent activity with MIC99 values of 6.25 µg/mL. To further understand the binding interactions, the synthesized compounds were docked against the tuberculosis protein 5OEQ using in silico molecular docking. Moreover, the most active compounds were additionally tested for their cytotoxicity against the RAW 264.7 cell line, and the cytotoxicity of compounds 3f, 3h, 3i, and 3o was 27.3, 28.9, 26.4, and 30.2 µg/mL, respectively. These results revealed that the compounds 3f, 3h, 3i, and 3o were less harmful to humans. Furthermore, the synthesized compounds were tested for ADME qualities, and the results suggest that this series is useful for producing innovative and potent anti-tubercular medicines in the future.

Design, synthesis and antitubercular assessment of 1, 2, 3-triazole incorporated thiazolylcarboxylate derivatives.

A library of 1, 2, 3-triazole incorporated thiazolylcarboxylate derivatives (7a-q) and (8a-j) were synthesized and evaluated for their in-vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The two compounds 7h and 8h have displayed excellent antitubercular activity with MIC values of 3.12 and 1.56 µg/mL respectively (MIC values of standard drugs; Ciprofloxacin 1.56 µg/mL & Ethambutol 3.12 µg/mL). Whereas, the four compounds 7i, 7n, 7p and 8i displayed noticeable antitubercular activity with a MIC value of 6.25 µg/mL. The active compounds of the series were further studied for their cytotoxicity against RAW264.7 cell line using MTT assay. Furthermore, to study the probable mechanism of antitubercular action, physicochemical property profiling, DFT calculation and molecular docking study were executed on mycobacterial cell wall target Decaprenylphosphoryl-ß-d-ribose 2'-epimerase 1 (DprE1). Among all the compounds, 7h (-10 kcal/mol) and 8h (-10.1 kcal/mol) exerted the highest negative binding affinity against the targeted DprE1 (PDB: 4NCR) protein.

In vitro and in silico exploration of newly synthesized triazolyl- isonicotinohydrazides as potent antitubercular agents.

In the present study, we have reported the synthesis of novel isoniazid-triazole derivatives (4a-r), via the click chemistry approach. The synthesized isoniazid-triazole derivatives have potent in vitro antitubercular activity against the Mycobacterium tuberculosis (MTB) H37Rv strain. Among these compounds, 4b, 4f, 4g, 4j, 4k, 4m, 4o, 4p, and 4r were found to be the most active ones with a MIC value of 0.78 µg/mL. This activity is better than ciprofloxacin (MIC value = 1.56 µg/mL) and ethambutol (MIC value = 3.12 µg/mL). The compounds, 4a, 4c, 4d, 4e, 4h, 4i, 4l, and 4n have displayed activity equal to ciprofloxacin (MIC value = 1.56 µg/mL). The cytotoxicity of the active isoniazid-triazole derivatives was studied against RAW 264.7 cell line by MTT assay at 25 µg/mL concentration and no toxicity was observed. Moreover, in-vitro results were supported by in-silico studies with the known antitubercular target (PanK). The drug-likeness, density functional study, molecular docking, and molecular dynamics simulation studies of isoniazid-triazole derivatives validated the ability to form a stable complex with Pantothenate kinase (PanK), which will result in inhibiting the Pantothenate kinase (PanK). Therefore, the results obtained indicate that this class of compounds may offer candidates for future development, and positively provide drug alternatives for tuberculosis treatment.Communicated by Ramaswamy H. Sarma.

New nitazoxanide derivatives: design, synthesis, biological evaluation, and molecular docking studies as antibacterial and antimycobacterial agents.

A new series inspired by combining fragments from nitazoxanide (NTZ) and 4-aminosalicylic acid (4-ASA) was synthesized and screened for in vitro antibacterial and antimycobacterial activities. The majority showed higher antibacterial potency than NTZ against all the screened strains, notably, 5f, 5j, 5n and 5o with MICs of 0.87-9.00 µM. Compounds 5c, 5n and 5o revealed higher potency than ciprofloxacin against K. pneumoniae, while 5i was equipotent. For E. faecalis, 3b, 5j, and 5k showed higher potency than ciprofloxacin. 5j was more potent against P. aeruginosa than ciprofloxacin, while 5n was more potent against S. aureus with an MIC of 0.87 µM. 5f showed equipotency to ciprofloxacin against H. pylori with an MIC of 1.74 µM. Compounds 3a and 3b (4-azidoNTZ, MIC 4.47 µM) are 2 and 5-fold more potent against Mycobacterium tuberculosis (Mtb H37Rv) than NTZ (MIC 20.23 µM) and safer. 4-Azidation and/or acetylation of NTZ improve both activities, while introducing 1,2,3-triazoles improves the antibacterial activity. Molecular docking studies within pyruvate ferredoxin oxidoreductase (PFOR), glucosamine-6-phosphate synthase (G6PS) and dihydrofolate reductase (DHFR) active sites were performed to explore the possible molecular mechanisms of actions. Acceptable drug-likeness properties were found. This study may shed light on further rational design of substituted NTZ as broad-spectrum more potent antimicrobial candidates.

Repurposing Azoles to Resolve Serotogenic Toxicity Associated with Linezolid to Combat Multidrug-Resistant Tuberculosis.

Serotogenic toxicity is a major hurdle associated with Linezolid in the treatment of drug-resistant tuberculosis (TB) due to the inhibition of monoamine oxidase (MAO) enzymes. Azole compounds demonstrate structural similarities to the recognized anti-TB drug Linezolid, making them intriguing candidates for repurposing. Therefore, we have repurposed azoles (Posaconazole, Itraconazole, Miconazole, and Clotrimazole) for the treatment of drug-resistant TB with the anticipation of their selectivity in sparing the MAO enzyme. The results of repurposing revealed that Clotrimazole showed equipotent activity against the Mycobacterium tuberculosis (Mtb) H37Rv strain compared to Linezolid, with a minimal inhibitory concentration (MIC) of 2.26 µM. Additionally, Clotrimazole exhibited reasonable MIC50 values of 0.17 µM, 1.72 µM, 1.53 µM, and 5.07 µM against the inhA promoter+, katG+, rpoB+, and MDR clinical Mtb isolates, respectively, compared to Linezolid. Clotrimazole also exhibited 3.90-fold less inhibition of MAO-A and 50.35-fold less inhibition of MAO-B compared to Linezolid, suggesting a reduced serotonergic toxicity burden.

Fluorescent Nanoassembly of Tetrazole-Based Dyes with Amphoteric Surfactants: Investigation of Cyanide Sensing and Antitubercular Activity.

Tetrazole-based easily synthesizable fluorogenic probes have been developed that can form self-assembled nanostructures in the aqueous medium. Though the compounds could achieve detection of cyanide ions in apolar solvents, such as, THF, significant interference was observed from other basic anions, such as F-, AcO-, H2PO4-, etc. On the other hand, a highly specific response was observed for CN- ions in the aqueous medium. However, the sensitivity was so poor that it could hardly be useful for real-life sample analysis. Interestingly, the co-assembly of such probe molecules with hydroxyethyl-anchored amphoteric surfactants could drastically improve the sensitivity toward CN- ions in water without dampening their excellent selectivity. Also, it was observed that the degree of fluorescence response for CN- ions depends on the nature of the polyaromatic scaffolds (naphthyl vs anthracenyl), the nature of the surfactant assembly (micelle vs vesicle), etc. The mechanistic investigation indicates the hydrogen bonding interaction between the tetrazole -NH group and cyanide ions in the aqueous medium, which can effectively change the electronics of the tetrazole unit, resulting in alteration in the extent of charge transfer interaction. Then, the biocompatible composite materials (dye-surfactant assemblies at different ratios) were tested for antituberculosis activity. Fortunately, in a few cases, the compositions were found to be as effective as the commercially available antituberculosis drug, ethambutol.

Isoflavonoid and Furanochromone Natural Products as Potential DNA Gyrase Inhibitors: Computational, Spectral, and Antimycobacterial Studies.

In pursuit of new antitubercular agents, we here report the antimycobacterial (H37Rv) and DNA gyrase inhibitory potential of daidzein and khellin natural products (NPs). We procured a total of 16 NPs based on their pharmacophoric similarities with known antimycobacterial compounds. The H37Rv strain of M. tuberculosis was found to be susceptible to only two out of the 16 NPs procured; specifically, daidzein and khellin each exhibited an MIC of 25 µg/mL. Moreover, daidzein and khellin inhibited the DNA gyrase enzyme with IC50 values of 0.042 and 0.822 µg/mL, respectively, compared to ciprofloxacin with an IC50 value of 0.018 µg/mL. Daidzein and khellin were found to have lower toxicity toward the vero cell line, with IC50 values of 160.81 and 300.23 µg/mL, respectively. Further, molecular docking study and MD simulation of daidzein indicated that it remained stable inside the cavity of DNA GyrB domain for 100 ns.

Canagliflozin protects diabetic cardiomyopathy by mitigating fibrosis and preserving the myocardial integrity with improved mitochondrial function.

Sodium-glucose transport protein 2 (SGLT-2) inhibitors are approved antidiabetic drugs with a beneficial effect on reducing major adverse cardiac events and heart failure hospitalization. Among them, canagliflozin has the least selectivity toward SGLT-2 over the SGLT-1 isoform. Canagliflozin can inhibit SGLT-1 at therapeutic levels; however, the underlying molecular mechanism is not understood. This study aimed to evaluate the effect of canagliflozin on SGLT1 expression in an animal model of diabetic cardiomyopathy (DCM) and its associated effects. In vivo studies were carried out in the most clinically relevant high-fat diet and streptozotocin-induced type-2 diabetes model of diabetic cardiomyopathy, and in vitro studies were performed using cultured rat cardiomyocytes stimulated with high glucose and palmitic acid. DCM was induced in male Wistar rats for 8 weeks with or without 10 mg/kg canagliflozin treatment. At the end of the study, systemic and molecular characteristics were measured using immunofluorescence, quantitative RT‒PCR, immunoblotting, histology, and FACS analysis. SGLT-1 expression was upregulated in DCM hearts and was associated with fibrosis, apoptosis, and hypertrophy. Canagliflozin treatment attenuated these changes. The histological evaluation showed improved myocardial structure, and in vitro results revealed improved mitochondrial quality and biogenesis after canagliflozin treatment. In conclusion, canagliflozin protects the DCM heart by inhibiting myocardial SGLT-1 and associated hypertrophy, fibrosis, and apoptosis. Thus, developing novel pharmacological inhibitors targeting SGLT-1 could be a better strategy for treating DCM and associated cardiovascular complications.

Synthesis, biological evaluation and molecular docking study of some new 4-aminosalicylic acid derivatives as anti-inflammatory and antimycobacterial agents.

In this study, new derivatives of the antitubercular and anti-inflammatory drug, 4-aminosaliclic acids (4-ASA) were synthesized, characterized, and evaluated for these activities. In vivo and in viro evaluation of anti-inflammatory activity revealed that compounds 10, 19 and 20 are the most active with potent cyclooxygenase-2 (COX-2) and 5-lipooxgenase (5-LOX) inhibition and without causing gasric lesions. The minimum inhibitory concentrations (MIC) of the newly synthesized compound were, also, measured against Mycobacterium tuberculosis H37RV. Among the tested compounds 17, 19 and 20 exhibited significant activities against the growth of M. tuberculosis. 20 is the most potent with (MIC 1.04 µM) 2.5 folds more potent than the parent drug 4-ASA. 20 displayed low cytotoxicity against normal cell providing a high therapeutic index. Important structure features were analyzed by docking and structure-activity relationship analysis to give better insights into the structural determinants for predicting the anti-inflammatory and anti-TB activities. Our results indicated that compounds 19 and 20 are potential lead compounds for the discovery of dual anti-inflammatory and anti-TB drug candidates.

Design and synthesis of novel quinazolinyl-bisspirooxindoles as potent anti-tubercular agents: an ultrasound-promoted methodology.

The essential need for the potent anti-tubercular (anti-TB) agents with high selectivity and safety profile prompted us to synthesize a new series of quinazolinyl-bisspirooxindoles. The title compounds were synthesized by one-pot multicomponent [3 + 2] cycloaddition reaction under ultrasonication. Further, in vitro anti-TB activity was evaluated against Mycobacterium tuberculosis H37Rv. Among the screened compounds, two compounds (4q and 4x) showed potent activity with MIC value 1.56 µg/mL and four compounds exhibited significant activity (MIC = 3.125 µg/mL), and also cytotoxicity studies against RAW 264.7 cell lines reveal that most active compounds were less toxic to humans. In addition, in order to demonstrate the inhibitory properties, molecular docking studies were carried out and the results showed that the target compounds have good binding energy and better binding affinity within the active pocket, thus these compounds may consider to be as potent inhibitors toward selective targets.

Aryl-n-hexanamide linked enaminones of usnic acid as promising antimicrobial agents.

Lichen secondary metabolites are well explored medicinal agents with diverse pharmacological properties. One of the important antibiotic lichen secondary metabolites is usnic acid. Its diverse medicinal profiles prompted us to explore it as a potential antitubercular molecule. Towards this direction, continuing our efforts on the discovery and development of new analogs with potent antitubercular properties we designed, synthesized, and evaluated a set of 37 usnic acid enaminone-coupled aryl-n-hexanamides (3-39). The study yielded a 3,4-dimethoxyphenyl compound (13, 5.3 µM) as the most active anti-TB molecule. The docking studies were performed on 7 different enzymes to better understand the binding modes, where it was observed that compound 13 bound strongly with glucose dehydrogenase (Gscore: - 9.03). Further antibacterial investigations revealed compound 2 with potent inhibition on Salmonella typhi and Bacillus subtilis (MIC 3 µM) and MIC values of 7 and 14 µM on Streptococcus mutans and Escherichia coli respectively. Compound 19 (3-F-5-CF3-phenyl) displayed encouraging antibacterial profiles against E. coli, S. typhi and S. mutans with MIC values of 10 µM respectively. Interestingly, compound 20 (2,6-difluorophenyl) also displayed good antibacterial activity against E. coli with an MIC value of 6 µM. These encouraging pharmacological results will help for better designing and developing usnic acid-based semi-synthetic derivatives as potential antimicrobial agents. A set of 37 new usnic acid enaminone-coupled aryl-n-hexanamides were synthesized and evaluated as potential antimicrobial agents. Compound 13 was identified as the most active antitubercular molecule. 13 was further docked against 7 different enzymes of tuberculosis. The molecule displayed maximum binding energy with the enzyme Glucose dehydrogenase (Gscore: - 9.03), indicating that these hexanamides possibly act by inhibiting the glucose metabolic pathway of the bacterium. Surprisingly, the intermediate hexanoic acid 2 was identified as potent antibacterial agent, acting on both gram-positive and gram-negative bacterial strains (3-14 µM). The active compounds may be subjected to structural iterations to develop further leads.

New tetrahydropyrimidine-1,2,3-triazole clubbed compounds: Antitubercular activity and Thymidine Monophosphate Kinase (TMPKmt) inhibition.

Two series of new tetrahydropyrimidine (THPM)-1,2,3-triazole clubbed compounds were designed, synthesized and screened for their antitubercular (anti-TB) activity against M. tuberculosis H37Rv strain using microplate alamar blue assay (MABA). The most active compounds 5c, 5d, 5e and 5f were further examined for their cytotoxicity against the growth of RAW 264.7 mouse macrophage cells using MTT assay. The four compounds showed safety profiles better than or comparable to that of ethambutol (EMB). These compounds were evaluated for their inhibition activity against mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Compounds 5c and 5e were the most potent exhibiting comparable inhibition activity to that of the natural substrate deoxythymidine monophosphate (dTMP). An in silico study was performed including docking of the most active compounds 5c and 5e into the TMPKmt (PDB: ID 1G3U) binding pocket in addition to prediction of their physicochemical and pharmacokinetic properties to explore the overall activity of these anti-TB candidates. Compounds 5c and 5e are promising anti-TB agents and TMPKmt inhibitors with acceptable oral bioavailability, physicochemical and pharmacokinetic properties.

Benzo[d]thiazole-2-carboxamides as new antituberculosis chemotypes inhibiting mycobacterial ATP phosphoribosyl transferase.

Aims: The screening of antimycobacterial benzo[d]thiazole-2-carboxamides against ATP-phosphoribosyl transferase (ATP-PRTase) was conducted. Materials & methods: The antitubercular potential of compounds 1 and 2 against ATP-PRTase was assessed through the determination of half maximal effective concentration (EC50) and binding constant (Kd), as well as competitive inhibitory studies and studies of perturbation of secondary structure, molecular modeling and L-histidine complementation assay. Results & conclusion: Compounds 1n and 2a significantly inhibited ATP-PRTase as evidenced by their EC50 and Kd values and the perturbation of the secondary structure study. Compound 1n exhibited stronger competitive inhibition toward ATP compared with 2a. The inhibition of the growth of Mycobacterium tuberculosis by targeting the L-histidine biosynthesis pathway and molecular modeling studies further supported the inhibition of ATP-PRTase.