DESIGN, SYNTHESIS AND MOLECULAR DOCKING STUDY OF HYBRID QUINOLINE-4-YL-OXADIAZOLES/OXATHIADIAZOLES AS POTENT ANTIFUNGAL AGENTS

Objective: The aim of the present work was to design and synthesize hybrid quinoline-4-yl-oxadiazoles/oxathiadiazole derivatives and evaluate them for in vitro antifungal activity against human disease causing pathogens.Methods: The compounds 5(a-d), 6(a-d) and 7(a-d) were efficiently synthesized in good yields. The synthesized compounds were characterized using 1H NMR, 13C NMR and Mass spectra. The synthesized compounds were screened for in vitro antifungal activity and minimum inhibitory concentration (MIC) values were determined using standard agar method. Molecular docking study was performed against fungal enzyme P450 cytochrome lanosterol 14α-demethylase using VLife MDS 4.3 software.Results: The synthesized compounds had shown good to moderate in vitro antifungal activity. The compound 6a (MIC range = 15-25 µg/ml) from 1,2,3,5-oxathiadiazole-2-oxide series showed most potent activity amongst the synthesized compounds when compared with standard clotrimazole (MIC range = 12.5-25 µg/ml). The molecular docking study of synthesized compounds showed good binding interactions against active site of fungal enzyme P450 cytochrome lanosterol 14α-demethylase.Conclusion: The results of in vitro antifungal activity and molecular docking study revealed that the synthesized compounds have potential antifungal activity and can be further optimized and developed as a lead compound.Â

Efficient one-pot synthesis, molecular docking and in silico ADME prediction of bis-(4-hydroxycoumarin-3-yl) methane derivatives as antileishmanial agents

Bis-(4-hydroxycoumarin-3-yl) methane derivatives 3(a-l) were synthesized from 4-hydroxycoumarin and substituted aromatic aldehydes using succinimide-N-sulfonic acid as catalyst and evaluated for their in vitro antileishmanial activity against promastigotes form of Leishmania donovani. Compounds 3a (IC50= 155 μg/mL), 3g (IC50= 157.5 μg/mL) and 3l (IC50= 150 μg/mL) were shown significant antileishmanial activity when compared with standard sodium stibogluconate (IC50= 490 μg/mL). Also, synthesized compounds 3(a-l) did not show cytotoxicity against HeLa cell line upto tested concentrations. Further, molecular docking study against Adenine phosphoribosyltransferase of Leishmania donovani showed good binding interactions. ADME properties were analyzed and showed good oral drug candidate like properties. The synthesized compounds were also shown good drug likeness and drug score values when compared with drugs currently used in therapy. The present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent

Ultrasound- and Molecular Sieves-Assisted Synthesis, Molecular Docking and Antifungal Evaluation of 5-(4-(Benzyloxy)-substituted phenyl)-3- ((phenylamino)methyl)-1,3,4-oxadiazole-2(3H)-thiones

A novel series of 5-(4-(benzyloxy)substituted phenyl)-3-((phenyl amino)methyl)-1,3,4-oxadiazole-2(3H)-thione Mannich bases 6a–o were synthesized in good yield from the key compound 5 (4(benzyloxy)phenyl)-1,3,4-oxadiazole-2(3H)-thione by aminomethylation with paraformaldehyde and substituted amines using molecular sieves and sonication as green chemistry tools. The antifungal activity of the new products was evaluated against seven human pathogenic fungal strains, namely, Candida albicans ATCC 24433, Candida albicans ATCC 10231, Candida glabrata NCYC 388, Cryptococcus neoformans ATCC 34664, Cryptococcus neoformans PRL 518, Aspergillus fumigatus NCIM 902 and Aspergillus niger ATCC 10578. The synthesized compounds 6d, 6f, 6g, 6h and 6j exhibited promising antifungal activity against the tested fungal pathogens. In molecular docking studies, derivatives 6c, 6f and 6i showed good binding at the active site of C. albicans cytochrome P450 enzyme lanosterol 14 α-demethylase. The in vitro antifungal activity results and docking studies indicated that the synthesized compounds have potential antifungal activity and can be further optimized as privileged scaffolds to design and develop potent antifungal drugsS

3D-QSAR, DOCKING STUDY, PHARMACOPHORE MODELING AND ADMET PREDICTION OF 2-AMINO-PYRAZOLOPYRIDINE DERIVATIVES AS POLO-LIKE KINASE 1 INHIBITORS

Objective: The polo-like kinase 1 (plk1) plays important roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation and cytokinesis. Thus, plk1 is considered as a good target for chemotherapeutic intervention. The main objectives of this research were to in silico screen the 2-amino-pyrazolopyridine derivatives as plk1 inhibitors and develop pharmacophore for enhanced activity. Methods: The three-dimensional quantitative structure–activity relationship (3D-QSAR), docking and pharmacophore identification studies on 2-amino-pyrazolopyridine derivatives as plk1 inhibitors have been carried out using V Life MDS 4.3 software. The stepwise 3D-QSAR kNN-MFA method was applied to derive QSAR model. Also, ADMET prediction was performed using FAF Drugs 2 which runs on Linux OS. Results: The information rendered by 3D-QSAR models may lead to a better understanding and designing of novel plk1 inhibitor molecules. The molecular docking analysis was carried out to better understand the interactions between plk1 enzyme and inhibitors in this series. Hydrophobic and hydrogen bond interactions lead to identification of active binding sites. The results of pharmacophore studies showed that hydrogen bond accepters, aromatic and aliphatic centers are the important features for polo-like kinase 1 inhibitor activity. ADMET prediction of these compounds showed good drug like properties. Conclusion: The combination of the 3D-QSAR, docking, pharmacophore modeling and ADMET prediction is an important tool in understanding the structural requirements for design of novel, potent and selective plk1 inhibitors and can be employed to design new  drug discovery and can be used for derivatives of 2-amino-pyrazolopyridines with specific plk1 inhibitory activity

Exploring antibiofilm potential of some new imidazole analogs against <i>C. albicans:</i> synthesis, antifungal activity, molecular docking and molecular dynamics studies

A series of 1, 2, 4, 5-tetrasubstituted imidazole derivatives were synthesized and their antibiofilm potential against Candida albicans was evaluated in vitro. Two of the synthesized derivatives 5e (IC50 = 25 µg/mL) and 5m (IC50 = 6 µg/mL),displayed better antifungal and antibiofilm potential than the standard drug Fluconazole (IC50 = 40 µg/mL) against C. albicans. Based on the in vitro results, we escalated the real time polymerase chain reaction (RT-PCR) analysis to gain knowledge of the enzymes expressed in the generation and maintenance of biofilms and the mechanism of biofilm inhibition by the synthesized analogues. We then investigated the possible interactions of the synthesized compounds in inhibiting agglutinin-like proteins, namely Als3, Als4 and Als6 were prominently down-regulated using in-silico molecular docking analysis against the previously available crystal structure of Als3 and constructed structure of Als4 and Als6 using the SWISS-MODEL server. The stability and energy of the agglutinin-like proteins–ligand complexes were evaluated using molecular dynamics simulations (MDS). According to the 100 ns MDS, all the compounds remained stable, formed a maximum of 3, and on average 2 hydrogen bonds, and Gibb’s free energy landscape analysis suggested greater affinity of the compounds 5e and 5m toward Als4 protein. Communicated by Ramaswamy H. Sarma</p