ABSTRACT
Aim: To synthesize and explore the therapeutic potential of amodiaquine analogues. Methodology: New promising analogues were synthesized by nucleophilic substitution at the 4-amino position and were characterized using 1H NMR, 13C NMR and FT-IR spectroscopic techniques. Results: Antibacterial and cytotoxic screening revealed the high potency of these compounds; analogue AS1 had an 34.3 ± 0.18 mm zone of inhibition against Pseudomonas aeruginosa. Excellent activity against fungal strains, that is, Candida albicans (39.6 ± 0.23 mm) was shown by analogue AS2. Analogue AS1 had an IC50 = 4.2 µg/ml against the HeLa cell line (cervical cancer) and binding energy against 5GWK (-8.32688 kcal/mol), 1PFK (-6.4780 kcal/mol) and 1TUP (-6.5279 kcal/mol) in the docking study. Conclusion: The obtained results reveal that these analogues exhibit potent antimicrobial and cytotoxic potential.
Subject(s)
Antineoplastic Agents , Uterine Cervical Neoplasms , Female , Humans , Molecular Structure , HeLa Cells , Structure-Activity Relationship , Amodiaquine/pharmacology , Uterine Cervical Neoplasms/drug therapy , Spectroscopy, Fourier Transform Infrared , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Candida albicans , Microbial Sensitivity Tests , Molecular Docking SimulationABSTRACT
BACE1 enzyme has been known a potential target involved in Alzheimer's disease (AD). Present research was focused on the principles of virtually screening, chemical synthesis and protease inhibitory effect of BACE1 enzyme via biaryl guanidine derivatives. In-silico based paradigm (ligand binding interaction within active domain of BACE 1 enzyme i.e., aspartate Asp32 and Asp228) a novel compound was synthesized and subsequently subjected to in-vitro and in-vivo evaluation. 1,3-di(isoquinolin-6-yl) guanidine was synthesized and found potent (IC50 6±0.56 µM) and active to arrest (99 %) ß-secretase enzyme (FRET assay). Furthermore, it was found to improve novel object recognition test (RTI =56.55%) and Morris water maze test (32.26±3.45s) significantly (p<0.05). Enhanced pharmacokinetics and related properties (high iLOGP and Log S =-3.98) along with improved permeation to the blood brain barrier (BBB) (zero Lipinski violation) made it feasible to inhibit BACE1 as a novel therapeutic source to treat AD in future.
Subject(s)
Alzheimer Disease , Amyloid Precursor Protein Secretases , Humans , Guanidine/pharmacology , Alzheimer Disease/drug therapy , Aspartic Acid Endopeptidases , GuanidinesABSTRACT
Aim of this study was to synthesize new inhibitors on the basis of active site of aspartic protease enzyme and to evaluate their intended biological activity. A3D model of an enzyme was generated via homology modeling and series of novel amide ligands were synthesized by using a short high yield process, subsequently, analyzed in-silico and in-vitro anti-leishmanial activities. Characterization and identification was accomplished via NMR (H1& C13), infrared and mass spectroscopic techniques. Among all compound (4) was found to show significant activity (IC50 58±0.01) against Leishmania major (L. major) species. Furthermore, docking studies confirmed the inhibition of a targeted enzyme that supported the interaction of potent compound (4) with key residues (aspartic protease) via hydrogen bonds. Present study conferred about novel compound (4) as a promising compound to antagonize L. major activities in future.
Subject(s)
Amides/chemical synthesis , Antiprotozoal Agents/chemical synthesis , Leishmania/drug effects , Molecular Docking Simulation/methods , Amides/metabolism , Amides/pharmacology , Antiprotozoal Agents/metabolism , Antiprotozoal Agents/pharmacology , Leishmania/metabolism , Ligands , Molecular Structure , Protein Structure, Secondary , Structure-Activity RelationshipABSTRACT
Malaria, dengue and chikungunya are the most rampant mosquito-borne infections predominantly in Pakistan. They pose a serious threat and cause a havoc for the victims owing to the life threatening signs and symptoms marked with elevated morbidity and mortality rate. It seems hard to discriminate due to common indications, consequently, deserves appropriate diagnosis prior elevated toll of death. Present article encompasses depth insights about their prevalence, diagnosis and clinical manifestation if erupt in the pandemic. However, host-vector-host cycle is the root cause of transmission and diverse mosquito species confer dissimilar infections. Indeed these infections are seasonal but other factors like flood, open irrigation channels, immense agricultural land, rich fauna and water reservoirs can't be overlooked. Dire need was felt to acknowledge and aware the public about local transmission, vector control, entomologic, research resources, diagnosis and advancement in healthcare system to alleviate them absolutely in future.
