Synthesis, Characterization, Molecular Docking Studies, and Biological Screening of Medicinal Compounds

Abstract

The metal complexes of the compounds have been used for medical applications in the history. Time and money spent in clinical development can be substantially reduce by working on metal complexes of already approved drugs. So, in the first part of thesis complexation of Metronidazole Benzoate (MTZ Benz) and Metronidazole (MTZ) drugs was done with copper metal in the presence of Dichloroacetic acid (DCA) as a ligand. The synthesized complexes of Metronidazole Benzoate (MTZ Benz or S-1) are [Cu2(OAc)4(MTZ Benz)2] or S-2, [Cu2(µDCA)2(DCA)2(MTZ Benz)4] or S-3, and of Metronidazole (MTZ or S-4) are included [(Cu2(OAc)4(MTZ)2)] or S-5 and [Cu2(µDCA)2(DCA)2(MTZ)] or S-6 complexes. Purity of the synthesized complexes was vindicated by melting point (m.p) and elemental analysis. Spectral analysis was performed by UV-Visible; Fourier transform infrared (FT-IR) and Mass spectrometry (MS) for the structural assignment of the synthesized complexes. In vitro investigations of antimicrobial potency of the synthesized complexes showed that the copper complexes of the drugs were more potent in the presence of DCA. However, Metronidazole (S-4) was found to be most potent against Saccharomyces cerevisiae fungus as compared to all the tested compounds with 19.9 mm inhibition zone. Complexes were found with significant inhibitory activities in α-amylase and α-glucosidase inhibition assays to exhibit their antidiabetic potentials. Antibacterial and α-amylase inhibition data was further exploited by molecular docking studies to confirm experimental results. The results of the activities suggested that these synthesized metal complexes can be used as bactericidal, fungicidal and antidiabetic agents in future. Two series of Schiff bases were synthesized in continuation of discovery of compounds with higher biological activity and improved selectivity to cope up the challenges of multidrug resistance in bacterial infection treatment,having antidiabetic, antioxidant, phytotoxic and have the potential to interact with DNA. First series comprised of 4-aminophenol derivatives, [i.e., (4-chloro-2-(((4-hydroxyphenyl)imino)methyl)phenol (S-1), 4-((4- (dimethylamino)benzylidene)amino)phenol (S-2), 4-((3-nitrobenzylidene)amino)phenol (S-3), 4-((thiophen-2-ylmethylene)amino)phenol (S-4), 4-((E)-3-phenylallylidene)amino)phenol (S 5)]. The second series comprised of hydrazine Schiff bases, [i.e., (1,2-dibenzyledene hydrazine (L-1), 4,4'-(hydrazine-1,2-diylidenebis(methan-1-yl-1-ylidene))bis(N,N-dimethylaniline) (L 2), 1,2-bis(thiophen-2-ylmethylene)hydrazine (L-3), 1,2-di((E)-pent-2-enylidene)hydrazine (L-4) and 1,2-bis((E)-3-phenylallylidene)hydrazine (L-5)]. Various analytical and spectral techniques were utilized for the characterization and structure elucidation of the synthesized derivatives, (i.e., melting point, elemental analysis, FT-IR, 1H NMR, and 13C NMR spectroscopy, etc.). Antibacterial (Gram-positive, Gram-negative bacteria) and antifungal (Saccharomyces cervesea fungus) activities were performed for all the synthesized derivatives of 4-aminophenol and broad spectrum activities were observed against all the tested strains. However, 1,2-di((E)-pent-2-enylidene)hydrazine (L-4) was observed comparatively with the best antimicrobial potential against all tested microbial strains. Significant α-amylase and α glucosidase inhibition but in concentration dependent manner was observed specially for 4- ((4-(dimethylamino)benzylidene)amino)phenol (S-2) and 4-chloro-2-(((4- hydroxyphenyl)imino)methyl)phenol (S-1), respectively. 4,4'-(hydrazine-1,2- diylidenebis(methan-1-yl-1- ylidene))bis(N,N-dimethylaniline) (L-2) was observed as better α amylase inhibitor. 1,2-bis((E)-3-phenylallylidene)hydrazine (L-5) with highest antioxidant (Phosphomolybdenum assay) potential (45 %) and 1,2-dibenzyledene hydrazine (L-1) with best phytotoxic activity (70 %) among all the tested hydrazine compounds. Deoxyribonucleic acid (DNA) interactions with 4-aminophenol Schiff bases exhibited intercalative binding mode, exhibited hyperchromic effect in spectral bands of S-1, S-2, S-3 and S-5 and hypochromic effect for of S-4 compound spectrum with bathochromic shifts in spectra of S-2, S-3 and S-4 Schiff bases. The overall aim of these investigations was the syntheses of medicinally important compounds, theoretically supported by computational studies to obtain such derivatives with high biological potentials (via metal complexation and via Schiff base preparation). The outcomes of this study proved that such kind of compounds can be pharmaceutically better options than the existing drugs. Further investigations on the reported biological potentials can be helpful in pharmacological field to discover new drug entities with better efficacy to cure diseases.