Investigation of new 1,2,3-triazolyl-quinolinyl-propan-2-ol derivatives as potential antimicrobial agents: in vitro and in silico approach.

A new series of 1-((1-(4-substituted benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2-substituted quinolin-4-yl)propan-2-ol (9a-x) have been synthesized. The newly synthesized 1,2,3-triazolyl-quinolinyl-propan-2-ol (9a-x) derivatives were screened for in vitro antimicrobial activity against M. tuberculosis H37Rv, E. coli, P. mirabilis, B. subtilis, and S. albus. Most of the compounds showed good to moderate antibacterial activity and all derivatives have shown excellent to good antitubercular activity with MIC 0.8-12.5 µg/mL. To know the plausible mode of action for antibacterial activity the docking study against DNA gyrase from M. tuberculosis and S. aureus was investigated. The compounds have shown significant docking scores in the range of -9.532 to -7.087 and -9.543 to -6.621 Kcal/mol with the DNA gyrase enzyme of S. aureus (PDB ID: 2XCT) and M. tuberculosis (PDB ID: 5BS8), respectively. Against the S. aureus and M. tuberculosis H37Rv strains, the compound 9 l showed good activity with MIC values of 62.5 and 3.33 µM. It also showed significant docking scores in both targets with -8.291 and -8.885 Kcal/mol, respectively. Molecular dynamics was studied to investigate the structural and dynamics transitions at the atomistic level in S. aureus DNA gyrase (2XCT) and M. tuberculosis DNA gyrase (5BS8). The results revealed that the residues in the active binding pockets of the S. aureus and M. tuberculosis DNA gyrase proteins that interacted with compound 9 l remained relatively consistent throughout the MD simulations and thus, reflected the conformation stability of the respective complexes. Thus, the significant antimicrobial activity of derivatives 9a-x recommended that these compounds could assist in the development of lead compounds to treat for bacterial infections.Communicated by Ramaswamy H. Sarma.

Synthesis, biological screening and in silico studies of new N-phenyl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine derivatives as potential antifungal and antitubercular agents.

A new series of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) have been synthesized by a cyclo-condensation reaction of 2-bromo-1-(1,3-diphenyl-1H-pyrazol-4-yl)ethanone (6a-f) with N-aryl thiourea, (7a-d). The structure of newly synthesized N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives was analyzed by 1H NMR, 13C NMR and Mass spectral analysis. The compounds 8a-x were screened for in vitro antimicrobial activity against Escherichia coli, Proteus mirabilis, Bacillus subtilis, Staphylococcus aureus, Candida albicans and Aspergillus niger. and antitubercular activity against M. tuberculosis H37Rv strain. Among the twenty-four pyrazolyl-thiazole derivatives, six compounds 8a, 8b, 8j, 8n, 8o and 8s showed good activity against S. aureus. Against A. niger, all synthesized derivatives showed good antifungal activity. Fifteen pyrazolyl-thiazole derivatives 8a, 8f, 8g, 8h, 8j, 8k, 8n, 8o, 8p, 8q, 8r, 8s, 8t, 8w and 8x showed good antitubercular activity with MIC 1.80-7.34 µM (0.8-3.12 µg/mL), these derivatives have showed more activity than the drugs isoniazid and ethambutol. The active compounds were further screened for cytotoxicity activity against the mouse embryonic fibroblast cells (3t3l1) cell lines at 12.5 and 25 µg/mL concentrations and found less or non-cytotoxicity. To know the plausible mode of action, the synthesized pyrazolyl-thiazole derivatives were studied for pharmacokinetics, toxicity profiles and binding interactions along with an in-depth analysis of structural dynamics and integrity using prolonged molecular dynamics (MD) simulation. The compounds have shown significant docking scores in the range of -7.98 to -5.52 and -9.44 to -7.2 kcal/mol with the M. tuberculosis enoyl reductase (M. tb. InhA) and C. albicans sterol 14-α demethylase (C. ab. CYP51), respectively. Thus, the significant antifungal and antitubercular activity of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives incited that, these scaffolds could assist in the development of lead compounds to treat fungal and antitubercular infections.

Synthesis of 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol as potential antimycobacterial agents.

Resistance to antibiotic drugs has directed global health security to a life-threatening situation due to mycobacterial infections. In search of a new potent antimycobacterial, a series of (±) 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a-p) have been synthesized. The structures of the newly synthesized derivatives were characterized by spectrometric analysis. Derivatives 8a-p were evaluated for antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC 25177), antibacterial activity against Proteus mirabilis (NCIM2388), Escherichia coli (NCIM 2065), Bacillus subtilis (NCIM2063) Staphylococcus albus (NCIM 2178) and antifungal activity against Candida albicans (NCIM 3100), Aspergillus niger (ATCC 504). Thirteen 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a-m) derivatives reported moderate to good antitubercular activity against M. tuberculosis H37Rv with MIC 9.2-106.4 µM. Compounds 8a and 8h showed comparable activity with respect to the standard drug pyrazinamide. The active compounds screened for cytotoxicity activity against L929 mouse fibroblast cells showed no significant cytotoxic activity. Compounds 8c, 8d, 8e, 8g, 8k, and 8o displayed good activity against S. albus. Compounds 8c and 8n showed good activity against P. mirabilis and E. coli, respectively. The potential antimycobacterial activities imposed that the 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol derivatives could lead to compounds that could treat tuberculosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-023-02741-3.

Synthesis and Biological Screening of New 2-(5-Aryl-1-phenyl-1H-pyrazol-3-yl)-4-aryl Thiazole Derivatives as Potential Antimicrobial Agents.

A new series of 2-(5-aryl-1-phenyl-1H-pyrazol-3-yl)-4-aryl thiazoles (10a-ab) have been synthesized by a cyclocondensation reaction of 5-aryl-1-phenyl-1H-pyrazole-3-carbothioamide (7a-d) with substituted phenacyl bromide (8a-f). The structure of newly synthesized 2-(5-aryl-1-phenyl-1H-pyrazol-3-yl)-4-aryl thiazole (10a-ab) derivatives was characterized by spectroscopic analysis. The compounds 10a-ab were evaluated for in vitro antibacterial activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus aureus (NCIM 2178), and in vitro antifungal activity against Aspergillus niger (ATCC 504) and Candida albicans (NCIM 3100). Among the twenty-eight pyrazolyl-thiazole derivatives, six compounds, 10g, 10h, 10i, 10j, 10o, and 10t, showed good activity against P. mirabilis; four compounds 10q, 10u, 10y, and 10z showed good activity against S. aureus; and twenty-four derivatives showed good antifungal activity against A. niger. Compounds 10g, 10q, 10r, 10s, and 10ab showed comparable activity with respect to the reference drug Ravuconazole. Thus, the significant antimicrobial activity of 2-(5-aryl-1-phenyl-1H-pyrazol-3-yl)-4-aryl thiazole (10a-ab) derivatives prompted that these scaffolds could assist in the development of lead compounds to treat microbial infections.

Synthesis, Characterization, and Antimicrobial Activity Screening of Some Novel 3-(2-(3-(Substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline Derivatives as Potential Antimycobacterial Agents.

Microbial infections remain a grave threat to global health security due to increasing antibiotic resistance. The coronavirus pandemic has increased the risk of microbial infection. To combat these infections, the search for new therapeutic agents is in high demand. A series of new 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline (9a-i) derivatives have been synthesized. The structure of synthesized compounds was analyzed by spectroscopic methods. The newly synthesized oxetanyl-quinoline derivatives were evaluated for in vitro antibacterial activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178), and in vitro antifungal activity against Aspergillus niger (ATCC 504) and Candida albicans (NCIM 3100). Six oxetanyl-quinoline derivatives 9a, 9b, 9c, 9d, 9e, and 9h have shown good antibacterial activity against P. mirabilis with MIC 31.25-62.5 µM, 3-(((3-(2-fluoro-6-((8-fluoro-2-methylquinolin-3-yl)oxy)phenyl)oxetan-3-yl)oxy)methyl)benzonitrile (9f) reporting comparable activity against P. mirabilis with respect to the standard drug streptomycin. Compound 9a also showed good activity against B. subtilis with MIC 31.25 µM. The eight compounds 9a, 9b, 9d, 9e, 9f, 9g, 9h, and 9i have shown good antifungal activity against A. niger. The synthesized compounds were also screened for antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MTT assay. Among the nine derivatives, compounds 9b, 9c, 9d, 9f, 9g, 9h, and 9i showed excellent antimycobacterial activity with MIC 3.41-12.23 µM, and two derivatives showed good activity with MIC 27.29-57.73 µM. All the derivatives were further evaluated for cytotoxicity against the Vero cell line and were found to be nontoxic. The in silico study of compounds 9a-i was performed against ATP synthase (PDB ID: 4V1F) and most of the compounds showed the stable and significant binding to ATP synthase, confirming their plausible mode of action as ATP synthase inhibitors. Thus, the significant antimycobacterial activity of 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline derivatives has suggested that the oxatenyl-quinoline compounds could assist in the development of lead compounds to treat mycobacterial infections.

In silico sequence analysis, homology modeling and function annotation of leishmanolysin from Leishmania donovani.

Leishmaniases are a complex of diseases that range from the deadly visceral disease and some self-curing lesions to gross disfigurations. About 12 million peoples from 88 different countries get infected by this protozoan parasite through the sand flies. Visceral leishmaniasis is a potentially fatal disease endemic to large parts of Asia and Africa, primarily caused by the protozoan parasite Leishmania donovani. L. donovani is a species of Leishmania, a hemoflagellate parasite and causative agent of visceral leishmaniasis. Leishmanolysin is the major surface protein of the parasitic Leishmania. Leishmanolysin has been described as a parasite virulence factor and is involved in the direct interaction of promastigotes and host macrophage receptors and interaction with the complement cascade. In the current study we predicted the 3D structure of leishmanolysin using homology modeling as 3D structure prediction approach. Leishmanolysin is a stable extracellular stable protein of 561 amino acid residues. 3D structure of the leishmanolysin was determined using Protein Structure Prediction Server (PS2 Server) selecting MODELLER as 3D structure prediction method. Quality analysis of the model through its Ramchandran Plot and ERRAT value (94.25) indicated that it is a reliable model. Functional annotation showed that this protein is a member of the superfamily cl18220. The information thus discussed provides insight to the molecular understanding of structure and function of leishmanolysin from L. donovani. The predicted 3-D model may be further used in characterizing the protein in wet laboratory.