Chemical profile, antituberculosis, DSC, and molecular docking studies of Mentha longifolia essential oil.

The volatile profile of Mentha longifolia was observed using GC-MS, GC-FID, FT-IR and 13CNMR. Twenty-two constituents were found to be present in this essential oil, accounting 96.04 (%) of total essential oil and oxegenated monoterpenes were major class of compounds. The key constituents of this essential oil were pieritenone oxide (45.9%), piperitone (17.5%), beta caryophyllene (10.2%), and Germacrene D (5.0%). FT-IR showed peak at 1669 and 1707 cm-1 which may be due to the presence of carbonyl groups. Among the tested compounds, Germacrene D showed highest binding affinity value of -6.8 kcal mol-1 and a pKi value of 6.01. The dsc studies revealed that boiling point of this EO is above 200 °C. Microplate Alamar Blue assay (MABA) was carried out for the assessment of antimycobacterial activity using isoniazid and nicotinic as reference compound and oil was found to be active within conc. range of 0.8-1.6 µg/mL against mycobacterium tuberculosis, hence can act as a potential candidate against antituberculosis.

Mycobacterial Targets for Thiourea Derivatives: Opportunities for Virtual Screening in Tuberculosis Drug Discovery.

Tuberculosis (TB) remains a primary global health concern, necessitating the discovery and development of new anti-TB drugs, mainly to combat drug-resistant strains. In this context, thiourea derivatives have emerged as promising candidates in TB drug discovery due to their diverse chemical structures and pharmacological properties. This review aimed to explore this potential, identifying and exploring molecular targets for thiourea derivatives in Mycobacterium tuberculosis (Mtb) and the potential application of virtual screening techniques in drug discovery. We have compiled a comprehensive list of possible molecular targets of thiourea derivatives in Mtb. The enzymes are primarily involved in the biosynthesis of various cell wall components, including mycolic acids, peptidoglycans, and arabinans, or targets in the branched-chain amino acid biosynthesis (BCAA) pathway and detoxification mechanisms. We discuss the potential of these targets as critical constituents for the design of novel anti-TB drugs. Besides, we highlight the opportunities that virtual screening methodologies present in identifying potential thiourea derivatives that can interact with these molecular targets. The presented findings contribute to the ongoing efforts in TB drug discovery and lay the foundation for further research in designing and developing more effective treatments against this devastating disease.

Clove Buds Volatile Compounds: Inhibitory Activity on Mycobacterium Growth and Molecular Docking on Mmr Efflux Pump Drug Resistance.

Syzygium aromaticum is used in traditional and modern medicine for its various and outstanding pharmacological properties. Here, we studied the chemical composition of hexane extract and non-polar fractions (NPF) obtained from the maceration and fractionation of clove buds, in order to evaluate their in vitro antimycobacterial activity, as well as their contribution against efflux pump (EP) resistance through molecular docking experiments. The gas chromatography-mass spectrometry (GC-MS) analysis of the volatile profiles revealed the presence of eugenol, followed by eugenyl acetate, and ß-caryophyllene as common major compounds. According to Resazurin microtiter assay (REMA), Mycobacterium tuberculosis H37 Rv strain was sensitive to all volatile samples at concentration range between 10 and 100 µg/mL. The NPF of ethanol extract was the best inhibitor with a MIC=10 µg/mL. The in silico study revealed a strong binding affinity between eugenol and Mmr EP protein (-8.1 Kcal/mol), involving two binding modes of hydrogen bond and π-alkyl interactions. The non-polarity character of clove volatile constituents, and their potential additive or synergistic effects could be responsible for the antimycobacterial activity. In addition, these findings suggest the benefic effect of eugenol in the management of mycobacterium drug resistance, whether as potential inhibitor of Mmr drug EP, or modulator during combination therapy.

Novel pyrimidine-1,3,4-oxadiazole hybrids and their precursors as potential antimycobacterial agents.

Background: Molecular hybridization and isostery are proven approaches in medicinal chemistry, and as such we used them to design novel compounds that we investigated as potential antimycobacterials to combat drug-resistant strains. Methods & results: Prepared N-alkyl-2-(pyrimidine-5-carbonyl)hydrazine-1-carboxamides were cyclized to N-alkyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amines along with their analogues. A total of 48 compounds were tested against Mycobacterium tuberculosis H37Rv, Mycobacterium avium and Mycobacterium kansasii, with oxadiazoles and C8-C12 alkyls being the most effective from a concentration of 2 µM. Multidrug-resistant strains were inhibited at same concentrations as the susceptible strain. For the most potent N-dodecyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amine, the mechanism of action related to cell wall biosynthesis was investigated. Conclusion: Pyrimidine-1,3,4-oxadiazole hybrids are unique antimycobacterial agents inhibiting mainly M. tuberculosis strains without cross-resistance to current drugs and are thus promising drug candidates.

Triad3A involved in the regulation of endotoxin tolerance and mycobactericidal activity through the NFκB-nitric oxide pathway.

INTRODUCTION: Sepsis is characterized by an endotoxin tolerance phenotype that occurs in the stage of infection. Persistent bacterial infection can lead to immune cell exhaustion. Triad3A, an E3 ubiquitin ligase, negatively regulates its activation by TLR4. However, the effect of Triad3A on endotoxin tolerance and bactericidal ability in the state of endotoxin tolerance remains unclear. METHODS: Using single dose LPS and repeated LPS stimulated macrophage cell lines at indicated times, we investigated miR-191, Tirad3A, TRAF3, TLR4, p-P65, TNF-α, IL-1ß, and iNOS expression, the effect of miR-191 on Triad3A and TRAF3, gene loss-of-function analyses, the effect of Triad3A on TLR4, p-P65, cytokine, and mycobactericidal activity in endotoxin tolerant cells infected with Mycobacterium marinum. RESULTS: Here we found that Triad3A is involved in regulating endotoxin tolerance. Our result also displayed that miR-191 expression is downregulated in macrophages in the state of endotoxin tolerance. miR-191 can directly bind to Triad3A and TRAF3. Additionally, knockdown of Triad3A can reverse the effect of decreasing TNF-α and IL-1ß in endotoxin tolerant macrophages. Furthermore, we demonstrated that the TLR4-NF-κB-NO pathway was associated with Triad3A and responsible for the killing of intracellular mycobacteria in a tuberculosis sepsis model. CONCLUSIONS: These results provide new insight into the mechanisms of Triad3A induced tolerogenic phenotype in macrophages, which can help the better comprehension of the pathogenesis involved in septic shock with infection of Mycobacterium tuberculosis, and suggest that Triad3A may be a potential drug target for the treatment of severe septic tuberculosis.

3-Methoxy-2-phenylimidazo[1,2-b]pyridazines highly active against Mycobacterium tuberculosis and Mycobacterium marinum.

A series of 3-methoxy-2-phenylimidazo[1,2-b]pyridazine derivatives which were highly active against autoluminescent Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm) in an in vitro assay were identified. SAR analysis showed that the most active compounds, which included a phenyl group bearing fluoro substituent(s) at C2, a methoxy function at C3, and a benzyl-heteroatom moiety at C6, exhibited in vitro MIC90 values generally around 0.63-1.26 µM against Mtb and Mm. However, these compounds were inactive against Mtb in vivo (mice), and investigations revealed very short metabolic half-lives (<10 min) when incubated with mouse liver microsomes. Multiple observations of side products produced from oxidative cleavage of the imidazole moiety during the chemical synthesis work suggested that this is a likely metabolic pathway leading to the lack of observed activity in vivo.

Synthesis and biological evaluation of 2-(Tetrazol-5-yl)sulfonylacetamides as inhibitors of Mycobacterium tuberculosis and Mycobacterium marinum.

A series of 2-(tetrazol-5-yl)sulfonylacetamide derivatives were synthesized and evaluated for their in vitro inhibitory activity against Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm). The most active compounds exhibited in vitro MIC90 values of 1.25 µg/mL against Mtb, but they were less effective against Mm (MIC90 ≥ 10 µg/mL). Despite the most active compounds having favourable physicochemical properties and one of them having a half-life of ∼3 h when incubated with mouse liver microsomes, two representative highly active compounds showed strong chemical reactivity to cysteine derivatives, as surrogate in vivo sulfur-centred nucleophiles, indicating excessive electrophilicity, and therefore, likely indiscriminate chemical reactivity in vivo, representing an unacceptably high risk of general toxicity, and low likelihood of being therapeutically effective.

Chemical analysis and antitubercular activity evaluation of the dried mycelial powders of the basidiomycete Ganoderma australe TBRC-BCC 22314.

The isolation of lanostane triterpenoids possessing significant anti-tuberculosis (anti-TB) activity from mycelial cultures of the basidiomycete Ganoderma australe strain TBRC-BCC 22314 was previously reported. To demonstrate the potential of the dried mycelial powder for utilization in anti-TB medicinal products, its authentic chemical analysis was performed. Considering the possibility of the changes in the lanostane compositions and anti-TB activity by sterilization, both autoclave treated and non-autoclaved mycelial powder materials were chemically investigated. The study led to the identification of the lanostanes responsible for the activity of the mycelial extract against Mycobacterium tuberculosis H37Ra. The anti-TB activity of the extracts from autoclaved and non-autoclaved mycelial powders were the same (MIC 3.13 µg/mL). However, the analytical results revealed several unique chemical conversions of the lanostanes under the sterilization conditions. The most potent major lanostane, ganodermic acid S (1), was shown to be significantly active also against the extensively drug-resistant (XDR) strains of M. tuberculosis.

Synthesis of Novel Benzenesulfonamide-Bearing Functionalized Imidazole Derivatives as Novel Candidates Targeting Multidrug-Resistant Mycobacterium abscessus Complex.

Infections caused by drug-resistant (DR) Mycobacterium abscessus (M. abscessus) complex (MAC) are an important public health concern, particularly when affecting individuals with various immunodeficiencies or chronic pulmonary diseases. Rapidly growing antimicrobial resistance among MAC urges us to develop novel antimicrobial candidates for future optimization. Therefore, we have designed and synthesized benzenesulfonamide-bearing functionalized imidazole or S-alkylated derivatives and evaluated their antimicrobial activity using multidrug-resistant M. abscessus strains and compared their antimycobacterial activity using M. bovis BCG and M. tuberculosis H37Ra. Benzenesulfonamide-bearing imidazole-2-thiol compound 13, containing 4-CF3 substituent in benzene ring, showed strong antimicrobial activity against the tested mycobacterial strains and was more active than some antibiotics used as a reference. Furthermore, an imidazole-bearing 4-F substituent and S-methyl group demonstrated good antimicrobial activity against M. abscessus complex strains, as well as M. bovis BCG and M. tuberculosis H37Ra. In summary, these results demonstrated that novel benzenesulfonamide derivatives, bearing substituted imidazoles, could be further explored as potential candidates for the further hit-to-lead optimization of novel antimycobacterial compounds.

Improving the antimicrobial activity of old antibacterial drug mafenide: Schiff bases and their bioactivity targeting resistant pathogens.

Background: Increasing rates of acquired resistance have justified the critical need for novel antimicrobial drugs. One viable concept is the modification of known drugs. Methods & results: 21 mafenide-based compounds were prepared via condensation reactions and screened for antimicrobial efficacy, which demonstrated promising activity against both Gram-positive and Gram-negative pathogens, pathogenic fungi and mycobacterial strains (minimum inhibitory concentrations from 3.91 µM). Importantly, they retained activity against a panel of superbugs (methicillin- and vancomycin-resistant staphylococci, enterococci, multidrug-resistant Mycobacterium tuberculosis) without any cross-resistance. Unlike mafenide, most of its imines were bactericidal. Toxicity to HepG2 cells was also investigated. Conclusion: Schiff bases were significantly more active than the parent drug, with iodinated salicylidene and 5-nitrofuran/thiophene-methylidene scaffolds being preferred in identifying the most promising drug candidates.

Synthesis, antitubercular evaluation, and molecular docking studies of hybrid pyridinium salts derived from isoniazid.

In the quest to develop potent inhibitors for Mycobacterium tuberculosis, novel isoniazid-based pyridinium salts were designed, synthesized, and tested for their antimycobacterial activities against the H37 Rv strain of Mycobacterium tuberculosis using rifampicin as a standard. The pyridinium salts 4k, 4l, and 7d showed exceptional antimycobacterial activities with MIC90 at 1 µg/mL. The in vitro cytotoxicity and pharmacokinetics profiles of these compounds were established for the identification of a lead molecule using in vivo efficacy proof-of-concept studies and found that the lead compound 4k possesses LC50 value at 25 µg/mL. The in vitro antimycobacterial activity results were further supported by in silico studies with good binding affinities ranging from -9.8 to -11.6 kcal/mol for 4k, 4l, and 7d with the target oxidoreductase DprE1 enzyme. These results demonstrate that pyridinium salts derived from isoniazid can be a potentially promising pharmacophore for the development of novel antitubercular candidates.

Bioactive Furanyl- or Thienyl-Substituted Nucleobases, Nucleosides and Their Analogues.

Five-membered heterocycles, including furan and thiophene, play a prominent role in drug design as structural units of bioactive molecules. This review is intended to demonstrate the importance of the furan-2-yl, furan-3-yl, thien-2-yl and thien-3-yl substituents in the medicinal chemistry of purine and pyrimidine nucleobases, nucleosides and selected analogues. Data presented in the article are limited to compounds containing heteroaromatic ring connected through a bond and not fused to other systems. The impact of bioisosteric replacement of aryl substituents with heteroaryl ones on activities was assessed by comparison of the title compounds with their aryl counterparts. A total of 135 heteroaryl-substituted and 35 aryl-substituted derivatives are mentioned in the text and shown in the figures. The following classes of compounds are included in the article: (i) 5-heteroaryl-2'-deoxyuridines and related compounds; (ii) 8-heteroaryl- 2,9-disubstituted adenine derivatives; (iii) O6-(heteroarylmethyl)guanines; (iv) 6-heteroaryl tricyclic guanine analogues; (v) 6-heteroaryl-9-benzylpurines and analogous compounds; (vi) N4- furfurylcytosine, N6-furfuryladenine, their derivatives and analogues; (vii) 6-heteroaryl purine and 7- deazapurine ribonucleosides; (viii) 7-heteroaryl-7-deazaadenosines, their derivatives and analogues; (ix) 4-heteroaryl fused 7-deazapurine nucleosides. In most cases various modifications of the lead compound structure performed in order to obtain the most favorable activity and selectivity are briefly discussed. The reviewed structure-activity relationship studies exemplify the search for compounds with optimized antiviral, antitumor, antimycobacterial or antiparkinsonian action.

Novel 5-Nitrofuran-Tagged Imidazo-Fused Azines and Azoles Amenable by the Groebke-Blackburn-Bienaymé Multicomponent Reaction: Activity Profile against ESKAPE Pathogens and Mycobacteria.

A chemically diverse set of 13 5-nitrofuran-tagged heterocyclic compounds has been prepared via the Groebke-Blackburn-Bienaymé multicomponent reaction. The testing of these compounds against the so-called ESKAPE panel of pathogens identified an apparent lead compound-N-cyclohexyl-2-(5-nitrofuran-2-yl)imidazo[1,2-a]pyridine-3-amine (4a)-which showed an excellent profile against Enterobacter cloacae, Staphylococcus aureus, Klebsiella pneumoniae, and Enterococcus faecalis (MIC 0.25, 0.06, 0.25 and 0.25 µg/mL, respectively). Its antibacterial profile and practically convenient synthesis warrant further pre-clinical development. Certain structure-activity relationships were established in the course of this study which were rationalized by the flexible docking experiments in silico. The assessment of antitubercular potential of the compounds synthesized against drug sensitive H37v strain of Mycobacterium tuberculosis revealed little potential of the imidazo-fused products of the Groebke-Blackburn-Bienaymé multicomponent reaction as chemotherapeutic agents against this pathogen.

Synthesis and Antimycobacterial Activity of Isoniazid Derivatives Tethered with Aliphatic Amines.

BACKGROUND: There is an urgent need for new antitubercular compounds. Modification of antimycobacterial isonicotinohydrazide at hydrazide N2 provided antimycobacterial active compounds. OBJECTIVE: Combining this scaffold with various aliphatic amines that are also frequently present in antitubercular compounds, we have designed, synthesized, and evaluated twenty-three N- (cyclo)alkyl-2-(2-isonicotinoylhydrazineylidene)propanamides and their analogues as potential antimycobacterial compounds. By increasing lipophilicity, we intended to facilitate the penetration of mycobacteria's highly impermeable cell wall. METHODS: The target amides were prepared via condensation of isoniazid and pyruvic acid, followed by carbodiimide-mediated coupling with yields from 35 to 98 %. The compounds were screened against Mycobacterium tuberculosis H37Rv and two nontuberculous mycobacteria (M. avium, M. kansasii). RESULTS: All the derivatives exhibited low minimum inhibitory concentrations (MIC) from ≤0.125 and 2 µM against M. tuberculosis and nontuberculous mycobacteria, respectively. The most active molecules were substituted by a longer n-alkyl from C8 to C14. Importantly, the compounds showed comparable or even several-fold lower MIC than parent isonicotinohydrazide. Based on in silico predictions, a vast majority of the derivatives share suitable physicochemical properties and structural features for drug-likeness. CONCLUSION: Presented amides are promising antimycobacterial agents.

Total Synthesis of the Antimycobacterial Natural Product Chlorflavonin and Analogs via a Late-Stage Ruthenium(II)-Catalyzed ortho-C(sp2)-H-Hydroxylation.

The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization's (WHO) goal to end the global TB pandemic by the year 2035. During the past 50 years, very few new drugs have been approved by medical agencies to treat drug-resistant TB. Therefore, the development of novel antimycobacterial drug candidates to combat the threat of drug-resistant TB is urgent. In this work, we developed and optimized a total synthesis of the antimycobacterial natural flavonoid chlorflavonin by selective ruthenium(II)-catalyzed ortho-C(sp2)-H-hydroxylation of a substituted 3'-methoxyflavonoid skeleton. We extended our methodology to synthesize a small compound library of 14 structural analogs. The new analogs were tested for their antimycobacterial in vitro activity against Mycobacterium tuberculosis (Mtb) and their cytotoxicity against various human cell lines. The most promising new analog bromflavonin exhibited improved antimycobacterial in vitro activity against the virulent H37Rv strain of Mtb (Minimal Inhibitory Concentrations (MIC90) = 0.78 µm). In addition, we determined the chemical and metabolic stability as well as the pKa values of chlorflavonin and bromflavonin. Furthermore, we established a quantitative structure-activity relationship model using a thermodynamic integration approach. Our computations may be used for suggesting further structural changes to develop improved derivatives.

Substituted N-phenylitaconamides as inhibitors of mycobacteria and mycobacterial isocitrate lyase.

Novel antimycobacterial drugs are needed, especially those with dual activity against both actively growing and non-replicating subpopulations of mycobacteria. Isocitrate lyase (ICL) is one of proposed targets and this enzyme is inhibited by itaconic acid. That is why we have designed and prepared sixteen amides of itaconic acid and various anilines and amine antimicrobial drugs to evaluate them as potential inhibitors of ICL and antimycobacterial agents. N-Phenylitaconamides were prepared from itaconic anhydride and substituted anilines (yields 57-99%). They were characterized and evaluated against mycobacterial ICL and against actively growing mycobacteria (M. tuberculosis H37Rv, M. avium, two strains of M. kansasii). All derivatives showed antimycobacterial efficacy with minimum inhibitory concentrations starting from 125 µM. M. kansasii was the most susceptible species. Itaconamides derived from sulfonamides or p-aminosalicylic acid were optimal for activity against extracellular mycobacteria. ICL1 was significantly inhibited by two compounds, with 2-methylene-4-[(4-nitrophenyl)amino]-4-oxobutanoic acid 1k being the most potent (36% inhibition at 10 µM), which was also more efficient than two comparators. Molecular docking revealed its mode of binding to the enzyme. Using in silico tools, physicochemical properties and structural features for drug-likeness and gastrointestinal absorption were evaluated.

Alkaloids of Dicranostigma franchetianum (Papaveraceae) and Berberine Derivatives as a New Class of Antimycobacterial Agents.

Tuberculosis (TB) is a widespread infectious disease caused by Mycobacterium tuberculosis. The increasing incidence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has created a need for new antiTB agents with new chemical scaffolds to combat the disease. Thus, the key question is: how to search for new antiTB and where to look for them? One of the possibilities is to search among natural products (NPs). In order to search for new antiTB drugs, the detailed phytochemical study of the whole Dicranostigma franchetianum plant was performed isolating wide spectrum of isoquinoline alkaloids (IAs). The chemical structures of the isolated alkaloids were determined by a combination of MS, HRMS, 1D, and 2D NMR techniques, and by comparison with literature data. Alkaloids were screened against Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. avium, M. kansasii, and M. smegmatis). Alkaloids 3 and 5 showed moderate antimycobacterial activity against all tested strains (MICs 15.625-31.25 µg/mL). Furthermore, ten semisynthetic berberine (16a-16k) derivatives were developed and tested for antimycobacterial activity. In general, the derivatization of berberine was connected with a significant increase in antimycobacterial activity against all tested strains (MICs 0.39-7.81 µg/mL). Two derivatives (16e, 16k) were identified as compounds with micromolar MICs against M. tuberculosis H37Ra (MIC 2.96 and 2.78 µM). All compounds were also evaluated for their in vitro hepatotoxicity on a hepatocellular carcinoma cell line (HepG2), exerting lower cytotoxicity profile than their MIC values, thereby potentially reaching an effective concentration without revealing toxic side effects.

Safety evaluation and bioassay-guided isolation of antimycobacterial compounds from Morella salicifolia root ethanolic extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Although the available medicines can cure almost all tuberculosis drug-susceptible patients some problems including the emergence of multi-drug resistant and extensively drug-resistant strains press for the need of new anti-TB medicines. Morella salicifolia is a common plant that is widely used in traditional medicine for managing HIV and AIDS-related conditions including tuberculosis but no studies have been done to evaluate its safety and efficacy. AIM OF THE STUDY: This study was designed to investigate the antimycobacterial activity and safety of M. salicifolia extract and its constituents. MATERIAL AND METHODS: Antimycobacterial activity of the crude extract was tested against non-pathogenic mycobacteria including Mycobacterium aurum (MA), Mycobacterium indicus pranii (MIP) and Mycobacterium madagascariense (MM) using the broth microdilution method. Bioassay-guided fractionation was employed to isolate the active compounds. Some of the isolated active compounds were tested for antimycobacterial activity against the standard and selected clinical isolates of M. tuberculosis. Safety of the crude extract was assessed using cytotoxicity assay and oral acute toxicity testing. RESULTS: The crude extract exhibited antimycobacterial activity against all the species used. The study led to isolation of six compounds; four pentacyclic triterpenoids; (3ß)-3-Hydroxyolean-12-en-28-oic acid (Oleanolic acid) (1), (2α,3ß)-2,3-Dihydroxyolean-12-en-28-oic acid (maslinic acid) (2), D-Friedoolean-14-ene-3ß,28-diol (taraxerol) (3), and D-Friedoolean-14-en-3ß-ol (myricadiol) (4), and two diarylheptanoids; (±)-myricanol (5) and myricanone (6). The six compounds exhibited activity against three nonpathogenic mycobacteria species. Compound 2, was the most active, with MICs of 17, 28 and 56 µg/ml against MM, standard a M. tuberculosis strain H37RV and rifampicin resistant M. tuberculosis clinical isolates, respectively. The crude extract did not show toxicity on peripheral blood mononuclear cells and it was safe in mice following acute oral toxicity test. CONCLUSION: The results from this study indicate that some isolated compounds in Morella salicifolia could form potential scaffolds for drug development efforts targeting M. tuberculosis. More studies are needed to further explore the potential of the plant extract and its secondary metabolites in the management of HIV and AIDS-related conditions using in-vivo models.

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole.

Antimicrobial drug resistance is currently one of the most critical health issues. Pathogens resistant to last-resort antibiotics are increasing, and very few effective antibacterial agents have been introduced in recent years. The promising drug candidates are often discontinued in the primary stages of the drug discovery pipeline due to their unspecific reactivity (PAINS), toxicity, insufficient stability, or low water solubility. In this work, we investigated a series of substituted N-oxazolyl- and N-thiazolylcarboxamides of various pyridinecarboxylic acids. Final compounds were tested against several microbial species. In general, oxazole-containing compounds showed high activity against mycobacteria, especially Mycobacterium tuberculosis (best MICH37Ra = 3.13 µg/mL), including the multidrug-resistant strains. Promising activities against various bacterial and fungal strains were also observed. None of the compounds was significantly cytotoxic against the HepG2 cell line. Experimental measurement of lipophilicity parameter log k'w and water solubility (log S) confirmed significantly (typically two orders in logarithmic scale) increased hydrophilicity/water solubility of oxazole derivatives in comparison with their thiazole isosteres. Mycobacterial ß-ketoacyl-acyl carrier protein synthase III (FabH) was suggested as a probable target by molecular docking and molecular dynamics simulations.

Development of New Antimycobacterial Sulfonyl Hydrazones and 4-Methyl-1,2,3-thiadiazole-Based Hydrazone Derivatives.

Fifteen 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives 3a-d and sulfonyl hydrazones 5a-k were synthesized. They were characterized by 1H-NMR, 13C NMR, and HRMS. Mycobacterium tuberculosis strain H37Rv was used to assess their antimycobacterial activity. All compounds demonstrated significant minimum inhibitory concentrations (MIC) from 0.07 to 0.32 µM, comparable to those of isoniazid. The cytotoxicity was evaluated using the standard MTT-dye reduction test against human embryonic kidney cells HEK-293T and mouse fibroblast cell line CCL-1. 4-Hydroxy-3-methoxyphenyl substituted 1,2,3-thiadiazole-based hydrazone derivative 3d demonstrated the highest antimycobacterial activity (MIC = 0.0730 µM) and minimal associated cytotoxicity against two normal cell lines (selectivity index SI = 3516, HEK-293, and SI = 2979, CCL-1). The next in order were sulfonyl hydrazones 5g and 5k with MIC 0.0763 and 0.0716 µM, respectively, which demonstrated comparable minimal cytotoxicity. All compounds were subjected to ADME/Tox computational predictions, which showed that all compounds corresponded to Lipinski's Ro5, and none were at risk of toxicity. The suitable scores of molecular docking performed on two crystallographic structures of enoyl-ACP reductase (InhA) provide promising insight into possible interaction with the InhA receptor. The 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives and sulfonyl hydrazones proved to be new classes of lead compounds having the potential of novel candidate antituberculosis drugs.