ChemInform Abstract: 4,5‐Dihydro‐1H‐pyrazolo[3,4‐d]pyrimidine Containing Phenothiazines as Antitubercular Agents.

Fifteen Streptomyces isolates were isolated from soil in some different location on vegetable plantation at agriculture standard condition. The isolates were assessed for their antibacterial activity against Mycobacterium tuberculosis (MTB) ATCC H37RV and mycobacterial which isolated from Dr. Soetomo Hospital patients in Surabaya. The Interna-tional Streptomyces Project 4 (ISP4) and Middlebrook 7H9 (MB7H9) wwere used as growth or fermentation medium. The screening of inhibition activity was performed using turbidimetry and spot-test on agar medium. Results shown that 33.3% of the isolates (5 isolates) have anti-mycobacterial activities. The first line anti tuberculosis drug rifampicin, (RIF), ethambutol (EMB), isoniazid (INH), and pyrazinamide (PZA) were used as standards or positive controls with concentration 20 ppm. Optical density of crude fermentation broth concentrated from five isolates relatively lower than five anti-tuberculosis drug activity standard, although their activities against some microbial were similar to the stand-ard at spot-test. The most efficient isolate shown anti-mycobacterial activity was Streptomyces B10 which identified as Streptomyces violaceousniger. In addition, fatty acid methyl ester (FAME) profile of gas chromatography-mass spec-trometry chromatogram of each isolates were studied and compared to Streptomyces spp.

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 0.78µg/mL. However, three compounds (3f, 3h, and 3o) exhibited potent activity with MIC99 values of 6.25µg/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 30.2µg/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.

There is a pressing need to discover novel anti-tuberculosis agents to combat emerging drug-resistant strains. Cryptolepis sanguinolenta, Lantana camara, and Zanthoxylum leprieurii have been identified as potential sources of anti-tuberculosis (TB) drug candidates. Previous studies have examined the metabolites and metabolic pathways in mycobacterial strains affected by methanolic extracts of these plants, but the specific active compounds responsible for the antimycobacterial activity, the effect on affected metabolites and metabolic pathways of mycobacterial cell cultures, remain unclear. Untargeted metabolic fingerprinting may help identify the active compounds. The objective of this study was to model the antimycobacterial activity of methanolic extracts of C. sanguinolenta, L.camara, and Z. leprieurii as a function of their UHPLC-MS fingerprints and determine whether specific peaks (compounds) in the fingerprints contributed significantly to the activity. In this study, fingerprints of 18 methanolic extracts from C. sanguinolenta roots, L.camara leaves, and Z. leprieurii stem barks were obtained with ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). The minimal inhibitory concentrations (MICs) of these extracts against a pan-sensitive M.tuberculosis strain were determined using a resazurin-based microdilution assay. Fingerprints were processed and analyzed using regions of interest-multivariate curve resolution (ROIMCR). Partial least squares (PLS) regression was employed to model the MICs. Potential active compounds, including cryptolepine (from C. sanguinolenta), verbascoside (from L.camara), and isofagaridine (from Z. leprieurii), were identified as antimycobacterial compounds. These compounds likely influence mycobacterial metabolic processes, including cell wall synthesis, protein production, nucleotide metabolism, and energy generation. Further investigations are required to validate our findings.

Rifamycins form a class of antibiotics with a specific potency as drug against tuberculosis via inhibition of the DNA-dependent RNA polymerase. In the present study, literature data on the antibacterial potency against Mycobacterium tuberculosis and other bacteria of 53 derivatives of 3-formyl rifamycin SV are subjected to a QSAR analysis using AM1-based quantum chemical descriptors and the recently introduced dynamic approach that allows explicit consideration of the conformational space of properly generated 3D structures. Data pre-treatment includes normalization of the minimum inhibition concentration (MIC) values of ordinary bacteria using the well-known antituberculosis drug rifampicine as reference compound (RIA), and averaging over the different strains as motivated by a mathematical analysis of the two-step inhibition process. For both this generalized potency against ordinary bacteria and the antimycobacterial activity, QSAR modelling yields 3-variable regression equations with acceptable statistics for screening purposes (r2 around 0.60), which however differ partly in the stepwise-selected molecular descriptors and the respective conformers. While both types of activity are increased by increasing HOMO energy reflecting an increased electron donor capability and tendency to undergo hydroquinone-semiquinone-quinone oxidation, the models differ in the best 2nd and 3rd local quantum chemical descriptors, pointing to partially conflicting electronic structure requirements for optimal antimycobacterial activity and generalized activity against other bacteria. The discussion includes a detailed mechanistic analysis of the underlying bioreactivity aspects.

We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.

Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of anti-infective agents. Herein, we report an optimised, high yield process for the preparation of various 2-arylnaphthoquinones by a palladium-catalysed Suzuki reaction. All synthesised compounds were evaluated for their in-vitro antiprotozoal and antimycobacterial activity. Antiprotozoal activity was assessed against Plasmodium falciparum (P.f.) NF54 and Trypanosoma brucei rhodesiense (T.b.r.) STIB900, and antimycobacterial activity against Mycobacterium smegmatis (M.s.) mc2 155. Substitution with pyridine and pyrimidine rings significantly increased antiplasmodial potency of our compounds. The 2-aryl-NQs exhibited trypanocidal activity in the nM range with a very favourable selectivity profile. (Pseudo)halogenated aryl-NQs were found to have a pronounced effect indicating inhibition of mycobacterial efflux pumps. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. In addition, the physicochemical parameters of the synthesised compounds were discussed.

<p>Three aspects of the protecting-group-free (PGF) synthesis of small molecules have been described in this thesis. In the first part, the PGF azasugar synthesis methodology was applied to 2-deoxy-D-glucose with the intention of selectively forming the six-membered azasugar 5-epi-fagomine. Surprisingly, four products were formed in the key I2-mediated carbamate annulation step, with a pyrrolidine being the major product after optimisation. This was formed in 15% yield. A mechanism that explains the formation of the four carbamates was proposed, which was supported by an investigation into related halocyclisation reactions. The next part of this thesis describes the development of a new PGF methodology for the synthesis of conduramines, another class of biologically interesting molecules. Conduramines are amino polyhydroxy cyclohexenes and some conduramines have glycosidase inhibitory activity. These molecules are also useful precursors to a variety of biologically useful molecules including aminocyclitols and azasugars. The key steps in the PGF synthesis of conduramines are a Vasella-Barbier amination, a reaction that forms new C-C and C-N bonds concomitantly, and a ring closing metathesis in the presence of free hydroxyl and amine groups. To this end, a 4-deoxy 3-conduramine was prepared in just four steps and in 27% yield. Finally, the preparation of an amine library and its biological testing for the identification of a new anti-tuberculosis drug is described. Two short syntheses were used to prepare alkenylamines and amines from the corresponding sugar, with various lipophilic groups attached to the amine. A 20-member amine library was prepared, and the compounds were tested for anti-mycobacterial activity in a mycobacterial growth inhibition assay. The most active compounds were subjected to further biological testing to determine their general cytotoxic properties. Two amines, arabinohexadecylamine and arabinohexadecylmethylamine, were identified as having the best potential for use as anti-tuberculosis drugs, and have been sent to Colorado State University for subsequent in vivo testing in a mouse model of tuberculosis.</p>

Background: Microwave-assisted organic synthesis has been a powerful and expedient tool for quick organic synthesis which has vital advantages such as simplicity in process, cumulative rate of reaction, high reaction yields, and less amount of side product etc. Multicomponent reactions have developed chemical transformations for powerful bond-forming in organic, combinatorial and medicinal chemistry. The spirooxindole system possesses prominent biological properties and played a very vital role as a core structure of many synthetic pharmaceuticals. Isatin and its derivatives are a leading molecule for designing latent bioactive agents. Isatin and its derivatives are used as precursors due to having numerous applications and great biological characteristics. Fused chromenes derivatives have established more attention because of their high potential biological application. Here, we have described a one-pot synthesis of diverse spiro[chromene-4,3’-indoline] derivatives using ZrSiO2 mediated three-component reactions of substituted phenols with isatin and malononitrile. Methods: We have used microwave assisted method for synthesis. We have taken mixture of phenol derivatives, Isatin, Malononitrile, the catalyst, ZrSiO2 (10 mol %) and 5 ml methanol was placed into a 25 mL round bottomed flask. The reaction mixture was irradiated under microwave radiations at 100 °C, 300 W for 3-7 min. The progress of the reaction was monitored by thin layer chromatographic plate. After consumption of all starting materials the mixture was poured into water and then extracted with ethyl acetate. The organic layer was washed with brine and evaporated under reduced pressure. The combined aqueous layer was filtered to recycle the catalyst. Filtered catalyst washed with methanol two or three times to remove the strains and tars, and then dried in an oven. Compounds were isolated by column chromatography, elution gradient 15% Ethyl acetate: hexane as pure yellow solid with 80-90% of yield. The catalyst was reused up to three cycles with slight decrease of catalytic activity. Antibacterial activity of synthesized compound was carried out on Nutrient- agar plates by well-diffusion assay against test culture. Results: The one pot three-component cyclization reaction of phenol derivatives, isatin and malononitrile in the presence of ZrSiO2 (10 mol %) as catalyst in methanol was performed and the reaction was completed in 3-7 minutes by using microwave irradiation to afford 2-amino-2'-oxospiro [chromene-4,3’-indoline]-3-carbonitrile 4a in good yields. First, we optimized catalyst for finding best catalyst in very short reaction time with high yields. Reactions using ZrSiO2 in methanol give desirable yield with 88 % in very short time. A sensible decrease in the product yield was observed only after the third recycle of the catalyst. The structures of all the newly synthesized compounds were confirmed by various spectroscopy techniques. All the synthesized compounds were screened through antibacterial activity. Most of the synthesized compounds found to be active against Gram negative bacteria and Gram positive bacteria. Conclusion: We have presented a series of 2-amino-2'-oxospiro[chromene-4,3'-indoline]-3-carbonitrile derivatives that have been synthesized by microwave assisted reaction by isatin, malononitrile and various phenol derivatives. We have described a facile, one pot, three component, and environmentally benign protocol using ZrSiO2 as a prompt catalyst which can be reused. Most important of all, the synthesized derivatives can be used for the development of new antibacterial drugs because compounds 4f, 4b and 4d exhibited promising activity as compared to streptomycin. Keywords: Isatin, microwave-assisted synthesis, multi-component reactions, spiro compound, ZrSiO2.

Problem statement: Tuberculosis is a leading global mortality factor which has not been effectively controlled, with 1.7 million deaths per year and 8.9 million new cases. Aerobic microbe Mycobacterium tuberculosis H37Rv (MTB) is the causative agent of tuberculosis . Although many active antitubercular agents have since been develo ped, drug resistance will continue to be a problem. Therefore, there is a clear need for the discovery of new derivatives with antitubercular activity for the management of tuberculosis. It was observed from the literature that pyridine nucleus have significant antitubercular activity. On the basis of that we ha ve synthesized some new derivatives of pyridines an d investigated their antimycobacterial properties. Approach: Two series of 3-cyano-4, 6-dimethyl-2- (Alkyl/Aryllthio) pyridine and 4, 6-dimethyl-2-(Alk yl/Aryllthio) nicotinamide have been designed and synthesized from malanonitrile. The title compounds were evaluated at 12.5, 25 and 100 µg mL -1 concentrations for their anti tubercular activity a gainst Mycobacterium tuberculosis H37 Rv using Lowenstein Jensen method (proportion method). Results: Many of the synthesized compounds exhibit significant anti tubercular activity in com parison to Isoniazide while other compounds have shown promising ant tubercular activity. All the sy nthesized compounds screened for antimycobacterial activity were found significantly active against M. tuberculosis at the concentration 12.5 µg mL -1 . Conclusion: The antituberculosis screening data revealed that a ll the tested compounds 3a-3d and 4a-4d showed moderate to very good inhibitory activity. The compounds 4a-4d showed very good antituberculosis activity. The good activity i s attributed to the presence of substituted alkyl g roup at position-2 and amide group at position-3 of pyri dine ring. Structure Activity Relationship (SAR) study reveals that with the increase in the chain l ength of alkyl group at position-2 has tremendously increased the activity of the title molecules.

Background:: Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is one of the most contagious and fatal human pathogens which necessitates the development of modified existing drugs or derivatives with action against novel targets. Aims and Objectives:: In the present work, we have explored a few, 2-(5-(substituted)-4H-1,2,4-triazole-2-ylthio)-N-(substituted) phenyl acetamide (5A-5E) derivatives as anti-TB. Materials and Methods:: On the basis of SAR were synthesized and screened against Mycobacterium tuberculosis H37Rv using MABA assay. Their ADME properties were also checked. Results:: ADME analysis showed results comparable with standard drug (rifampicin). Derivative 5D turned out to be the most active amongst all the derivatives with MIC of 0.8μg/ml, comparable to standard drugs like rifampicin(0.8μg/ml) and streptomycin(0.8μg/ml). Conclusion:: All five compounds have shown excellent inhibitory activity (1.6μg/ml) against the Mycobacterium tuberculosis H37Rv strain. Compound 5D shows a promising activity (0.8μg/ml) as compared to standard drugs and also it has shown the highest docking score. Literature search has revealed the presence of 1,2,4-triazole derivatives linked to aromatic link and possessing amide linkage and the presence of Sulphur atom in the most active derivatives, which supports our designed compounds. Based on these findings, further derivatives would be synthesized and explored for their role in tuberculosis.

8-Nitro-1,3-benzothiazin-4-ones (BTZs) are known as potent antitubercular agents. BTZ043 as one of the most advanced compounds has reached clinical trials. The putative oxidation products of BTZ043, namely, the corresponding BTZ sulfoxide and sulfone, were reported in this journal (Tiwari et al. ACS Med. Chem Lett. 2015, 6, 128-133). The molecular structures were later revised to the constitutionally isomeric benzisothiazolone and its 1-oxide, respectively. Here, we report two BTZ043-derived benzisothiazolinones (BITs) with in vitro activity against mycobacteria. The constitutionally isomeric O-acyl benzisothiazol-3-ols, in contrast, show little or no antimycobacterial activity in vitro. The structures of the four compounds were investigated by X-ray crystallography and NMR spectroscopy. Molecular covalent docking of the new compounds to Mycobacerium tuberculosis decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) suggests that the active BITs exert antimycobacterial activity through inhibition of DprE1 like BTZs.

ABSTRACTA family of arylspiroborate compounds has been prepared from 2,3‐dihydroxynaphthalene and characterized fully using multinuclear NMR spectroscopy and elemental analyses. Single crystal X‐ray diffraction studies were carried out on the tetramethylammonium (4) and calcium (6) derivatives. Compound 6 represents the first structurally characterized example of a calcium arylspiroborate salt. All compounds showed modest antifungal and antimycobacterial activities. These results have revealed a new class of compounds that should be further developed to design more potent and selective antitubercular agents. © 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:116–123, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21072

In this study, wereport the design and synthesis of a series ofnovel thiophene-arylamide compounds derived from the noncovalent decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) inhibitor TCA1 througha structure-based scaffold hopping strategy. Systematic optimizationof the two side chains flanking the thiophene core led to new leadcompounds bearing a thiophene-arylamide scaffold with potent antimycobacterialactivity and low cytotoxicity. Compounds 23j, 24f, 25a, and 25b exhibited potent in vitro activity against both drug-susceptible (minimuminhibitory concentration (MIC) = 0.02–0.12 μg/mL) anddrug-resistant (MIC = 0.031–0.24 μg/mL) tuberculosisstrains while retaining potent DprE1 inhibition (half maximal inhibitoryconcentration (IC50) = 0.2–0.9 μg/mL) andgood intracellular antimycobacterial activity. In addition, thesecompounds showed good hepatocyte stability and low inhibition of thehuman ether-à-go-go related gene (hERG) channel. The representativecompound 25a with acceptable pharmacokinetic propertydemonstrated significant bactericidal activity in an acute mouse modelof tuberculosis. Moreover, the molecular docking study of templatecompound 23j provides new insight into the discoveryof novel antitubercular agents targeting DprE1.

New quinolin-4-yl-1,2,3-triazoles carrying amides, sulphonamides and amidopiperazines as potential antitubercular agents

Chlorophyll triggered one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones via photo induced electron transfer reaction