Exploring rhodanine linked enamine-carbohydrazide derivatives as mycobacterial carbonic anhydrase inhibitors: Design, synthesis, biological evaluation, and molecular docking studies.

With the rise of multidrug-resistant tuberculosis, the imperative for an alternative and superior treatment regimen, incorporating novel mechanisms of action, has become crucial. In pursuit of this goal, we have developed and synthesized a new series of rhodanine-linked enamine-carbohydrazide derivatives, exploring their potential as inhibitors of mycobacterial carbonic anhydrase. The findings reveal their efficacy, displaying notable selectivity toward the mycobacterial carbonic anhydrase 2 (mtCA 2) enzyme. While exhibiting moderate activity against human carbonic anhydrase isoforms, this series demonstrates promising selectivity, positioning these compounds as potential antitubercular agents. Compound 6d was the best one from the series with a Ki value of 9.5 µM toward mtCA 2. Most of the compounds displayed moderate to good inhibition against the Mtb H37Rv strain; compound 11k showed a minimum inhibitory concentration of 1 µg/mL. Molecular docking studies revealed that compounds 6d and 11k show metal coordination with the zinc ion, like classical CA inhibitors.

Exploring and exploiting the host cell autophagy during Mycobacterium tuberculosis infection.

Tuberculosis, caused by Mycobacterium tuberculosis, is a fatal infectious disease that prevails to be the second leading cause of death from a single infectious agent despite the availability of multiple drugs for treatment. The current treatment regimen involves the combination of several drugs for 6 months that remain ineffective in completely eradicating the infection because of several drawbacks, such as the long duration of treatment and the side effects of drugs causing non-adherence of patients to the treatment regimen. Autophagy is an intracellular degradative process that eliminates pathogens at the early stages of infection. Mycobacterium tuberculosis's unique autophagy-blocking capability makes it challenging to eliminate compared to usual pathogens. The present review discusses recent advances in autophagy-inhibiting factors and mechanisms that could be exploited to identify autophagy-inducing chemotherapeutics that could be used as adjunctive therapy with the existing first-line anti-TB agent to shorten the duration of therapy and enhance cure rates from multidrug-resistant tuberculosis (MDR-TB) and extreme drug-resistant tuberculosis (XDR-TB).

Exploration of 3-aryl pyrazole-tethered sulfamoyl carboxamides as carbonic anhydrase inhibitors.

Herein, we report the design and synthesis of two series of pyrazole-tethered sulfamoyl phenyl acetamides and pyrazole-tethered sulfamoyl phenyl benzamides. The synthesized compounds were investigated for inhibiting two human carbonic anhydrases, human carbonic anhydrases (hCA) I and II, and those of the bacterial pathogen Mycobacterium tuberculosis, mtCA 1-3. The results indicate that, among the synthesized compounds, pyrazoles with 4-aminobenzene sulfonamide were more selective toward hCA I and II over mtCAs, and compounds with 3-aminobenzene sulfonamide were selective toward mtCA 1-3 over hCA I, II. Compound 6g showed significant and selective inhibition toward hCA I and II, with Ki values of 0.0366 and 0.0310 µM, respectively. Compound 5g exhibited the best inhibition toward mtCA 2, with a Ki value of 0.0617 µM. Among the benzamides, compound 9b exhibited significant activity toward mtCA 2, with a Ki value of 0.0696 µM. Selectivity of these compounds was further supported by docking studies. When tested for antitubercular activity, many compounds showed moderate to good inhibition against the Mtb H37Rv strain, with minimum inhibitory concentration (MIC) values in the range of 4-128 µg/mL.

Antitubercular activity of 2-mercaptobenzothiazole derivatives targeting Mycobacterium tuberculosis type II NADH dehydrogenase.

Mycobacterium tuberculosis (Mtb) type II NADH dehydrogenase (NDH-2) transports electrons into the mycobacterial respiratory pathway at the cost of reduction of NADH to NAD+ and is an attractive drug target. Herein, we have synthesised a series of 2-mercaptobenzothiazoles (C1-C14) and evaluated their anti-tubercular potential as Mtb NDH-2 inhibitors. The synthesised compounds C1-C14 were evaluated for MIC90 and ATP depletion against Mtb H37Ra, M. bovis, and Mtb H37Rv mc2 6230. Compounds C3, C4, and C11 were found to be the active molecules in the series and were further evaluated for their MIC90 against Mtb-resistant strains and for their bactericidal potential against Mtb H37Rv mc26230. The Peredox-mCherry-expressing Mtb strain was used to examine whether C3, C4, and C11 possess NDH-2 inhibitory potential. Furthermore, cytotoxicity analysis against HepG2 displayed a safety index (SI) of >10 for C3 and C4. To get an insight into the mode of interaction at NDH-2, we have performed computational analysis of our active compounds.

Development and Evaluation of Bis-benzothiazoles as a New Class of Benzothiazoles Targeting DprE1 as Antitubercular Agents.

Benzothiazole-bearing compounds have emerged as potential noncovalent DprE1 (decaprenylphosphoryl-ß-d-ribose-2'-epimerase) inhibitors active against Mycobacterium tuberculosis. Based on structure-based virtual screening (PDB ID: 4KW5), a focused library of thirty-one skeletally diverse benzothiazole amides was prepared, and the compounds were assessed for their antitubercular activity against M.tb H37Ra. Most potent compounds 3b and 3n were further evaluated against the M.tb H37Rv strain by the microdilution assay method. Among the compounds evaluated, bis-benzothiazole amide 3n emerged as a hit molecule and demonstrated promising antitubercular activity with minimum inhibitory concentration (MIC) values of 0.45 µg/mL and 8.0 µg/mL against H37Ra and H37Rv, respectively. Based on the preliminary hit molecule (3n), a focused library of 12 more bis-benzothiazole amide derivatives was further prepared by varying the substituents on either side to obtain new leads and generate a structure-activity relationship (SAR). Among these compounds, 6a, 6c, and 6d demonstrated remarkable antitubercular activity with MIC values of 0.5 µg/mL against H37Ra and 1.0, 2.0, and 8.0 µg/mL against H37Rv, respectively. The most active compound, 6a, also displayed significant efficacy against four drug-resistant tuberculosis strains. Compound 6a was assessed for in vitro cytotoxicity against the HepG2 cell line, and it displayed insignificant cytotoxicity. Furthermore, time-kill kinetic studies demonstrated time- and dose-dependent bactericidal activity of this compound. The GFP release assay revealed that compound 6a targets the inhibition of a cell wall component. SNPs in dprE-1 gene assessment revealed that compound 6a binds to tyrosine at position 314 of DprE1 and replaces it with histidine, causing resistance similar to that of standard TCA1. In silico docking studies further suggest that the strong noncovalent interactions of these compounds may lead to the development of potent noncovalent DprE1 inhibitors.

Multifunctional Wound Curation Dressing Material FemuFrost─An Antioxidant-Loaded Nanoemulsion Frosted Patch of Poly(vinyl alcohol) and Hyaluronic Acid.

The wound curation dressing material should own explicit elements to aggrandize wound cessation. The cryogel of poly(vinyl alcohol) (PVA) and hyaluronic acid (HA) is deemed to promote the angiogenesis, production of extracellular matrix components, granulation, and epithelialization. The research aims to tailor and evaluate the composite PVA/HA cryogel ingrained ferulic acid-loaded nanoemulsion patch labeled as PH-FemuFrost to improve the therapeutic properties and mechanical strength of the patches. The PH-FemuFrost exhibited a water uptake capacity of 268 ± 15.07%, porosity of 70.52 ± 7.4%, and 48.62 ± 2.2% in vitro degradation. The texture analysis revealed the improved mechanical properties of PH-FemuFrost in terms of burst strength and stiffness. The PH-FemuFrost exhibited in vitro antioxidant and antimicrobial activity against Staphylococcus aureus and Candida albicans species. The wound healing efficiency of PH-FemuFrost patches was significantly increased than blank PVA-HA patches. The groups treated with PH-FemuFrost exhibited a dense network of collagen type 1 in comparison to negative and PVA-HA groups. The normal skin and healed skin exhibited parallel arrangement of type I collagen fibers toward the skin. The levels of inflammatory mediators such as IL-6 (p value < 0.0001), IL-22 (p value 0.0098), and TNF-α levels (p value < 0.0001) of PH-FemuFrost is significantly reduced compared to the negative group.

Role of transcription termination factor Rho in anti-tuberculosis drug discovery.

Mycobacterial infections, including multidrug and extreme drug-resistant (MDR and XDR) infections, are a severe challenge and create a virtual antibiotic-deficient era. Bacterial transcription is an established antimicrobial drug target. In mycobacteria, efficient transcription termination relies on the ATP-dependent RNA helicase factor Rho. Rho factor is essential for Mycobacterium tuberculosis (Mtb) survival, and is a valid antibacterial drug target with no homolog in eukaryotes. Rho maintains genomic stability and virulence and prevents pervasive transcription in Mtb. In this review, we provide an overview of the essentiality of Rho in Mtb, which makes it an attractive drug target for inhibitor discovery.

Tweaking host immune responses for novel therapeutic approaches against Mycobacterium tuberculosis.

In TB, combat between the human host and Mycobacterium tuberculosis involves intricate interactions with immune cells. M. tuberculosis has evolved a complex evasion system to circumvent immune cells, leading to persistence and limiting its clearance by the host. Host-directed therapies are emerging approaches to modulate host responses, including inflammatory responses, cytokine responses, and autophagy, by using small molecules to curb mycobacterial infections. Targeting host immune pathways reduces the chances of antibiotic resistance to M. tuberculosis because, unlike antibiotics, this approach acts directly on the cells of the host. In this review, we discuss the role of immune cells during M. tuberculosis proliferation, provide a updated understanding of immunopathogenesis, and explore the range of host-modulating options for the clearance of this pathogen.

Unravelling the flexibility of Mycobacterium tuberculosis: an escape way for the bacilli.

The persistence of Mycobacterium tuberculosis makes it difficult to eradicate the associated infection from the host. The flexible nature of mycobacteria and their ability to adapt to adverse host conditions give rise to different drug-tolerant phenotypes. Granuloma formation restricts nutrient supply, limits oxygen availability and exposes bacteria to a low pH environment, resulting in non-replicating bacteria. These non-replicating mycobacteria, which need high doses and long exposure to anti-tubercular drugs, are the root cause of lengthy chemotherapy. Novel strategies, which are effective against non-replicating mycobacteria, need to be adopted to shorten tuberculosis treatment. This not only will reduce the treatment time but also will help prevent the emergence of multi-drug-resistant strains of mycobacteria.

Synthesis and pharmacological evaluation of 1,3-diaryl substituted pyrazole based (thio)urea derivatives as potent antimicrobial agents against multi-drug resistant Staphylococcus aureus and Mycobacterium tuberculosis.

The urgent development of newer alternatives has been deemed a panacea for tackling emerging antimicrobial resistance effectively. Herein, we report the design, synthesis, and biological evaluation of 1,3-diaryl substituted pyrazole-based urea and thiourea derivatives as antimicrobial agents. Preliminary screening results revealed that compound 7a (3,4-dichlorophenyl derivative) exhibited potent activity against S. aureus (MIC = 0.25 µg mL-1) and compound 7j (2,4-difluorophenyl derivative) against Mycobacterium tuberculosis (MIC = 1 µg mL-1). Compounds 7a and 7j were non-toxic to Vero cells with a favorable selectivity index of 40 and 200, respectively, and demonstrated good microsomal stability. Compound 7a exhibited equipotent activity (MIC = 0.25 µg mL-1) against various multidrug-resistant strains of S. aureus, which include various strains of MRSA and VRSA, and elicited bacteriostatic properties. In an enzymatic assay, 7a effectively inhibited DNA gyrase supercoiling activity at a concentration of 8 times MIC. Further, molecular modeling studies suggested that compound 7a binds at the active site of DNA gyrase with good affinity.