Synthesis, biological evaluation, and In silico molecular docking of N-(4-(4-substitutedphenyl)-6-(substituted aryl) pyrimidin-2-yl)-2-(2-isonicotinoyl hydrazinyl) acetamide.

Isonicotinohydrazide is the first-line medication in the prevention and treatment of tuberculosis. Antitubercular, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial activity, anticancer, antineoplastic activity, and anti-HIV activity are all demonstrated by drugs with a pyrimidine ring. The current study focuses on the synthesis of N-(4-(substituted-phenyl)-6-(substituted-aryl) pyrimidin-2-yl)-2-(2-isonicotinoylhydrazinyl) acetamide from isonicotinohydrazide. Newly synthesized compounds were characterized by spectral studies (IR, 1 H-NMR, 13 C-NMR, and mass spectroscopy). They were screened for their antituberculosis, antimalarial, and antiprotozoal activities and compared with standard drugs. Molecular docking of isonicotinohydrazide-bearing pyrimidine motifs was also done for some of the active compounds.

Microwave produced 8-methyl-1,2,4,8-tetraazaspiro[4.5]dec-2-en-3-amine derivatives: their in vitro and in silico analysis.

Compound 1 is formed by a microwave-assisted multicomponent reaction of 1-methylpiperidin-4-one, 2-amino-4-methoxy-6-methyl-1,3,5-triazine, and thiosemicarbazide, followed by the synthesis of Schiff base 2a-l with a variety of aldehydes. A comparison was made between the conventional and microwave methods, and the microwave approach was shown to be considerably superior to the classical method since it takes less time and produces higher yields. Several spectral investigations, including 1H NMR, 13C NMR, Mass, and IR spectroscopy, are used to characterize the complete series. In vitro antibacterial testing suggests that compounds 2c, 2f, and 2g are promising antibacterial agents, although compounds 2d, 2e, and 2l are effective antimycobacterial agents when compared to the conventional medicine Rifampicin. The docking score from docking studies is considerable, which validates the results of the biological examination. Molecular docking was performed on Escherichia coli DNA gyrase. According to the in silico ADME analysis, each drug molecule is ideal for use in terms of drug solubility, hydrogen bonding, and cell permeability.

Benzopyrazine-Based Small Molecule Inhibitors As Trypanocidal and Leishmanicidal Agents: Green Synthesis, In Vitro, and In Silico Evaluations.

World Health Organization (WHO) identified twenty tropical disease categories as neglected tropical diseases (NTDs). Chagas' disease (also known as American trypanosomiasis) and leishmaniasis are two major classes of NTDs. The total number of mortality, morbidity, and disability attributed each year due to these two categories of diseases in magnitudes is much higher than the so-called elite diseases like cancer, diabetes, AIDS, cardiovascular and neurodegenerative diseases. Impoverished communities around the world are the major victim of NTDs. The development of new and novel drugs in the battle against Chagas' disease and leishmaniasis is highly anticipated. An easy and straightforward on-water green access to synthesize benzopyrazines is reported. This ultrasound-assisted procedure does not require any catalyst/support/additive/hazardous solvents and maintains a high atom economy. A series of eleven benzopyrazines has been synthesized, and most of the synthesized compounds possess the drug-likeness following Lipinski's "Rule of 5". Benzopyrazines 3 and 4 demonstrated moderate leishmanicidal activity against L. mexicana (M378) strain. The selective lead compound 1 showed good leishmanicidal, and trypanocidal activities (in vitro) against both L. mexicana (M378) and T. cruzi (NINOA) strains compared to the standard controls. The in vitro trypanocidal and leishmanicidal activities of the lead compound 1 have been validated by molecular docking studies against four biomolecular drug targets viz. T. cruzi histidyl-tRNA synthetase, T. cruzi trans-sialidase, leishmanial rRNA A-site, and leishmania major N-myristoyl transferase.

Synthesis, biological evaluation and molecular dynamics studies of 1,2,4-triazole clubbed Mannich bases.

The present work highlightsthe synthesis of a newer biologically active Mannich bases contributing 4-((4-fluorobenzylidene)amino)-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol and various heterocyclic amines via N-Mannich reaction by the conventional method as well as microwave heating approach as a part of an environmentally benign synthetic protocol. All the synthesized compounds were characterized by spectral analysis and were screened for in vitro antimicrobial, antitubercular and antiprotozoal activity. The compound 4k was found to be most active respectively against S. aureus (MIC 12.5 µM) and C. albicans (MIC 100 µM). The derivative 4 g displayed potency against L.mexicana and T. cruzi with IC50 value 1.01 and 3.33 µM better than reference drug Miltefosina and Nifurtimox. The compound 4b displayed excellent potency against M. tuberculosis (MIC 6.25 µM) in the primary screening. The computational studies revealed for that Mannich derivative (4b) showed a high affinity toward the active site of enzyme which provides a strong platform for new structure-based design efforts. The Lipinski's parameters showed good drug-likeness properties and can be developed as an oral drug candidate.

Synthesis, In silico Molecular Docking and Pharmacokinetic Studies, In vitro Antimycobacterial and Antimicrobial Studies of New Imidozolones Clubbed with Thiazolidinedione.

BACKGROUND: A series of (E)-5-(4-((Z)-4-substitutedbenzylidene-2-thienylmethylene-5-oxo- 2-phenyl-4,5-dihydro-1H-imidazol-1-yl) benzylidene)thiazolidine-2,4-diones were synthesized and evaluated for antimycobacterial and antimicrobial activity. All these ligands were docked against protein (InhA) Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, (PDB ID: 4COD). OBJECTIVE: In this report, we have designed and synthesized azole scaffolds with good antitubercular activities as there is a real need to develop new candidates with less toxicity and more efficiency toward pathogen. The obtained antimycobacterial activity data have been validated in the terms of ligand-protein interaction and were also analyzed for ADME properties to determine their potential to build up as good oral drug candidates. METHODS: All the synthesized compounds have been established by elemental analysis, IR, 1H NMR, 13C NMR and Mass spectral data. In vitro antimycobacterial activity was carried out against (M. tuberculosis) H37Rv strain using Lowenstein-Jensen medium and antimicrobial activity against two gram-positive bacteria (S. aureus, S. pyogenes), two gram-negative bacteria (E. coli, P. aeruginosa) and three fungal species (C. albicans, A. niger, A. clavatus) using the broth microdilution method. In silico molecular docking studies were carried out using Glide (grid-based ligand docking) program incorporated in the Schrödinger molecular modeling package by Maestro 11.0 and ADME properties of synthesized compounds was performed using DruLito software. RESULTS: Compounds 3a, 3b, 3d, 3g, 3i and 3n exhibited promising antimicrobial activity whereas compound 3n showed very good antimycobacterial activity along with Gilde docking score (-8.864) and with the one violation in Lipinski's rule of five. CONCLUSION: The wet lab result for compound 3n along with Glide XP docking score and the calculated ADME parameters give the best choice for the preparation of new derivatives in order to improve antitubercular activity in future with more improved potency.

In vitro and in vivo assessment of newer quinoxaline-oxadiazole hybrids as antimicrobial and antiprotozoal agents.

A new series of N-(substituted-phenyl)-2-[5-(quinoxalin-2-yloxymethyl)-[1,3,4] oxadiazol-2-ylsulfanyl]-acetamides (5a-o) was designed and synthesised from the parent compound 2-hydroxy quinoxaline (1) through a multistep reaction sequence and was characterised by spectral and elemental analyses. All of the compounds synthesised were evaluated for their antimicrobial and antiprotozoal activities. The results revealed that quinoxaline-based 1,3,4-oxadiazoles displayed promising antibacterial, antifungal and anti-Trypanosoma cruzi activities compared with reference drugs, particularly the lead compound 5l in a short-term in vivo model in T. cruzi.

New 2-benzylsulfanyl-nicotinic acid based 1,3,4-oxadiazoles: their synthesis and biological evaluation.

A novel series of 5-(2-benzylsulfanyl-pyridin-3-yl)-2-(substituted)-sulfanyl-1,3,4-oxadiazoles 6a-j were synthesized from key intermediate 5-(2-benzylsulfanyl-pyridin-3-yl)-3H-[1,3,4]oxadiazole-2-thione 5. Nucleophilic substitution reactions with different electrophiles (E+), such as haloacetate and haloalkyl groups, were performed to get target compounds 6a-j. Compounds were characterized by NMR, mass, IR spectra and C, H, N analyses. All compounds were evaluated for their antimicrobial and antimycobacterial activities; selected analogs were screened for their anticancer activity on 60 tumor cell lines at single dose 1.00(-5) M. Unfortunately, none of the compounds showed a significant antitumor activity on 60 human tumor cell lines. However, compounds 6g and 6f with benzothiazole moiety (12.5 and 25 µg/ml) showed promising activity against Escherichia coli compared to ampicillin; compounds 6d, 6j bearing triazole and morpholine, respectively, showed promising antitubercular activity (25 µg/ml) compared to rifampicin.

Synthesis of s-triazine-based thiazolidinones as antimicrobial agents.

A novel series of thiazolidinone derivatives, namely 4-{4-dimethylamino-6-[4-oxo-2-phenyl-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-thiazolidin-3-yl]-[1,3,5]-triazin-2-yloxy}-1-methyl-1H-quinolin-2-ones, have been synthesized from the key intermediate 4-(4-amino-6-dimethylamino-[1,3,5]-triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (5). Compound 5 was condensed with various aldehydes to give Schiff base derivatives, which after cyclization gave thiazolidinones that were linked with 1-pyridin-2-yl-piperazine to obtain the target compounds. The newly synthesized compounds were evaluated for their antimicrobial activity against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri) and four fungi (Aspergillus niger, Candida albicans, Aspergillus fumigatus, Aspergillus clavatus).

Synthesis and in vitro antimicrobial evaluation of pyrazolyl-quinazolin-4(3H)-ones.

A new series of 2-[2-(2,6-dichlorophenyl)amino]phenyl methyl -3-[(1-phenyl-5-substituted phenyl)-5-hydro-1H-pyrazol-3-yl-amino]-6,8-dibromoquinazolin-4(3H)-ones C1-13 have been synthesized by the reaction of 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-substituted phenyl chromene amido-6,8-dibromo-quinazolin-4(3H)-ones with phenylhydrazine in the presence of glacial acetic acid. The chalcones B1-13 have been synthesized by the condensation of 2-[2-(2, 6-dichloro phenyl)amino]phenylmethyl-3-acetamido-6,8-dibromoquinazolin-4(3H)-one A with different substituted aromatic aldehydes. The structures of newly synthesized compounds have been confirmed on the basis of their elemental analysis and spectral data: IR, 'H NMR, (13)C NMR. All the compounds have been screened for antibacterial and antifungal activity.

Synthesis of novel 5-alkyl/aryl/heteroaryl substituted diethyl 3,4-dihydro-2H-pyrrole-4,4-dicarboxylates by aziridine ring expansion of 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters.

A novel synthetic methodology has been developed for the synthesis of diethyl 5-alkyl/aryl/heteroaryl substituted 3,4-dihydro-2H-pyrrole-4,4-dicarboxylates (also called 2-substituted pyrroline-4,5-dihydro-3,3-dicarboxylic acid diethyl esters) by iodide ion induced ring expansion of 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters in very good to excellent yields under mild reaction conditions. The electronic and steric impact of the substituents on the kinetics of ring expansion of N-vinyl aziridines to pyrrolines has been studied. Various diversely substituted novel pyrroline derivatives have been synthesized by this methodology and the products can be used as key intermediates in the synthesis of substituted pyrrolines, pyrroles and pyrrolidines.

Synthesis of 1,2,4-triazole derivatives containing benzothiazoles as pharmacologically active molecule.

In attempt to make significant pharmacologically active molecule, we report here the synthesis and in vitro antimicrobial and antitubercular activity of various series of 3-(3-pyridyl)-5-(4-nitrophenyl)-4-(N-substituted-1,3-benzothiazol-2-amino)-4H-1,2,4-triazole. The antimicrobial activity of title compounds were examined against two Gram-positive bacteria (Staphylococcus aureus, Streptococcus pyogenes), two Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), and three fungi (Candida albicans, Aspergillus niger, Aspergillus clavatus) using the broth microdilution method and antitubercular activity H(37)Rv using Lowenstein-Jensen agar method.

Synthesis of new 1,3-oxazolyl-7-chloroquinazolin-4(3H)ones and evaluation of their antimicrobial activities.

2-[2-(2,6-Dichlorophenyl)amino]phenylmethyl-3-{4-[(substituted phenyl)amino]-1,3-oxazol-2-yl)-7-chloroquinazolin-4(3H)ones 5a-o have been prepared from 2-[(2,6-dichloro phenyl)amino]phenyl acetic acid 1, which was converted to acid chloride 2 and cyclized with anthranilic acid afforded benzoxazin-4(H)ones 3. Further reaction with urea gave carboxamide-7-chloroquinazolin-4(3H)ones 4 cyclized with substituted phenyl acetamide a-o. All the compounds have been confirmed by elemental analysis, IR, NMR spectral data and evaluated for antimicrobial activity. Compounds 5o, 5k, and 5m (R = 1-H, 2,5-(Cl), and 2-Cl, 4-NO2) showed good activity, compared with the standard drugs.

New 4-thiazolidinones of nicotinic acid with 2-Amino-6-methylbenzothiazole and their biological activity.

The title compounds 6aâj, 2-[(6-methyl-1,3-benzothiazol-2-yl)amino]-N-[2-(substituted phenyl/furan-2-yl)-4-oxo-1,3-thiazolidin-3-yl]nicotinamides, were prepared from 2-chloropyridine-3-carboxylic acid (1) and 2-amino-6-methyl-benzothiazole (2) by known methods. All the compounds have been established by IR, (1)H NMR, (13)C NMR and elemental analyses. The in vitro antimicrobial screening of the compounds were carried out against two Gram positive (S. aureus, S. pyogenes), two Gram negative (E. coli, P. aeruginosa) bacteria and three fungal species (C. albicans, A. niger, A. clavatus) using the broth microdilution method. Some of the compounds are comparable with standard drugs.

Synthesis and antimicrobial activity of 3-(1,3,4-Oxadiazol-2-yl)quinazolin-4(3H)-ones.

In attempt to find new pharmacologically active molecules, we report here the synthesis and in vitro antimicrobial activity of various 3-(1,3,4-oxadiazol-2-yl)-quinazolin-4(3H)-ones. The antimicrobial activity of title compounds were examined against two gram positive bacteria (S. aureus, S. pyogenes), two gram negative bacteria (E. coli, P. aeruginosa) and three fungi (C. albicans, A. niger, A. clavatus) using the broth microdilution method. Some derivatives bearing a bromo or iodo group exhibited very good antimicrobial activity.

Antimycobacterial and antimicrobial study of new 1,2,4-triazoles with benzothiazoles.

In this study, we report the antimycobacterial and antimicrobial evaluation of newly synthesized 3-(3-pyridyl)-5-(4-methoxyphenyl)-4-(N-substituted-1,3-benzothiazol-2-amino)-4H-1,2,4-triazole 6a-j in good yields. All the synthesized compounds have been established by elemental analysis, IR, ¹H NMR, ¹³C-NMR and Mass spectral data. In-vitro antimycobacterial activity was carried out against (Mycobacterium tuberculosis) H37Rv strain using Lowenstein-Jensen medium and antimicrobial activity against two Gram positive bacteria (Staphylococcus aureus, Streptococcus pyogenes), two Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and three fungal species (Candida albicans, Aspergillus niger, Aspergillus clavatus) using the broth microdilution method. Compounds 2e, 6a, 6g, 6h, and 6j exhibited promising antimicrobial activity whereas compound 6j showed very good antimycobacterial activity.

Sulfonamides of 2-[(2,6-dichlorophenyl)amino]phenyl acetoxyacetic acid and their antibacterial studies.

Abstract: Reaction of 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetyl chloride 2 with various N'-(substituted aryl)-p-aminobenzenesulfonamide derivatives afforded title compounds. All the final compounds were characterized by the IR spectral data and elemental analysis and screened for antibacterial activity against Gram positive and Gram negativebacterial strains.

Pharmacological evaluation and characterizations of newly synthesized 1,2,4-triazoles.

The triazole analogs were obtained via. multistep synthesis sequence beginning with ethyl nicotinoate 3 which on treatment with hydrazine hydrate yields nicotinoyl hydrazide 4. Intermolecular cyclisation of 4 with 4-methylbenzoic acid in presence of phosphorous oxy chloride affords 2-(3-pyridyl)-5-(4-methylphenyl)-1,3,4-oxadiazole 5. Condensation of 5 with various substituted 2-hydrazino benzothiazole 2a-j results in 3-(3-pyridyl)-5-(4-methylphenyl)-4-(N-substituted-1,3-benzothiazol-2-amino)-4H-1,2,4-triazole 6a-j analogs. All the compounds have been characterized by elemental analysis, IR, (1)H NMR, (13)C NMR and mass spectral data. In vitro antitubercular activity was carried out against Mycobacterium tuberculosis H(37)Rv strain using Lowenstein-Jensen medium and antimicrobial activity against various bacteria and fungi using broth microdilution method. Compounds 2e, 6a, 6b, 6c, 6d, 6g, 6h and 6i emerged as promising antimicrobials. It was also observed that the promising antimicrobials have proved to be better antituberculars. Compound 6j showed better antitubercular activity compared to rifampicin.

Synthesis and microbial studies of (4-oxo-thiazolidinyl) sulfonamides bearing quinazolin-4(3H)ones.

2-[(2,6-Dichlorophenyl)amino]phenylacetic acid (A) on reaction with thionyl chloride gave corresponding acid chloride (B). A series of (4-oxo-thiazolidinyl)sulfonamides of quinazolin-4(3H)ones (4a-l) were prepared from Schiff bases (3a-l) of 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[(4-aminophenyl)sulfonamido-1-yl]quinazolin-4(3H)one (D) and substituted aromatic aldehyde. Newly synthesized compounds have been examined on the basis of elemental analysis, IR, 1H NMR and 13C NMR spectra. Antibacterial activity (minimum inhibitory concentration - MIC) against Gram-positive (S. aureus & S. pyogeneus) and Gram-negative (P. aeruginosa and E. coli) bacteria, as well as antifungal acivities (MIC) against C. albicans, A. niger and A. clavatus were determined by broth dilution method. Some of the compounds were endowed with a remarkable antibacterial as well as antifungal acivities.

Synthesis and in vitro antimicrobial study of Schiff base and thiazolidinone of 1-cyclopropyl-6-fluoro-7-[4-(2,3-dichlorophenyl)piperazin-1-yl]-4-quinolone.

The title compounds, 2-substituted phenyl-3-{1-cyclopropyl-6-fluoro-7-[4-(2,3-dichlorophenylpiperazin-1-yl]-4-oxo-1,4-dihydroquinoline} carboxamido-1,3-thiazolidin-4-ones 6a-j, have been synthesized after several structural variations viz. hydrazide 2 via acid chloride, Schiff base formation and cyclization of Schiff base followed by condensation with N-(2,3-dichlorophenyl)piperazine from the lead molecule 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-carboxylic acid 1. The synthesized compounds were tested for their antibacterial and antifungal activity (MIC) in vitro against organisms viz. S. aureus, S. pyogenes, E. coli, P. aeruginosa, C. albicans, A. niger and A. clavatus taking gentamycin, ampicillin, chloramphenicol, ciprofloxacin, norfloxacin, nystatin and greseofulvin as standard drugs. Compounds 4i, 5i and 6j (2-Cl, 2-Cl and 4-Cl) demonstrated excellent activity compared with ampicillin.