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Synthesis, Docking and In-Vitro Screening of Mannich Bases of Thiosemicarbazide for Anti-Fungal Activity

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Synthesis, Docking and In-Vitro Screening of Mannich Bases of Thiosemicarbazide for Anti-Fungal Activity View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Arabian Journal of Chemistry (2013) xxx, xxx–xxx King Saud University Arabian Journal of Chemistry www.ksu.edu.sa www.sciencedirect.com ORIGINAL ARTICLE Synthesis, docking and in-vitro screening of mannich bases of thiosemicarbazide for anti-fungal activity Sachin A. Pishawikar *, Harinath N. More Department of Pharmaceutical Chemistry, Bharti Vidyapeeth College of Pharmacy, Near Chitranagari Kolhapur, Maharashtra 416 013, India Received 14 December 2012; accepted 21 October 2013 KEYWORDS Abstract Mannich bases and thiosemicarbazide individually show antimicrobial, antifungal, anti- Antifungal; convulsant, antimalarial, analgesic and anti-inflammatory type of varied pharmacological activities. Brain heart infusion; The novelty of the present work is the synthesis of mannich bases of thiosemicarbazide as mutual Mannich bases; prodrugs. In step-1, mannich bases are synthesized using aldehyde, ketones and amines with ali- Thiosemicarbazide phatic, aromatic, cyclic and heterocyclic nature. In step-2, the synthesized bases were condensed with thiosemicarbazide to form mannich bases of thiosemicarbazide. Structural characterization of synthesized compounds was done using IR, mass and H-NMR spectroscopy. The compounds were screened for anti-fungal activity using BHI (brain heart infusion) broth dilution method against Candida albicans and Apergillus niger. Docking of synthesized compounds was done on CYP51A1, P45014DM (Lanosterol 14 a-demethylase enzyme) using Vlife MDS 3.5 to conform the mechanism of antifungal activity. Docking study showed a strong hydrophobic interaction between amino acid residues Arganine (ARG141), Glutamine (GLU146), Leucine (LEU54), Lycine (LYC227), and Threonine (THR147) with the carbon of ketone, nitrogen of amine and sulfur of thiosemicarbazide. Strong Vander wall’s interactions are also observed with the carbon of ketone, nitrogen of amine and sulfur of thiosemicarbazide. Analogs with aromatic and substituted aromatic aldehydes showed least activity, while analogs with aliphatic aldehyde, ketones and amines showed greater activity in C. albicans compared to A. niger. Analogs having morpholine as amine showed comparable activity in both. Compounds K17, K18, K19, and K20 have shown comparable highest activities. Crown Copyright ª 2013 Published by Elsevier Ltd. All rights reserved. 1. Introduction * Corresponding author. Tel.: +91 231 2637286, mobile: +91 9823751341; fax: +91 231 2638833. Infectious diseases caused by bacteria and fungi affect millions E-mail address: [email protected] (S.A. Pishawikar). of people worldwide. Systematic programs to discover and de- Peer review under responsibility of King Saud University. velop new antibiotics and antifungals, are the need of the hour due to considerable extent of development of resistance by organisms to the existing drugs used against them. Further, Production and hosting by Elsevier the need has arisen largely due to advent of HIV, which has 1878-5352 Crown Copyright ª 2013 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.arabjc.2013.10.016 Please cite this article in press as: Pishawikar, S.A., More, H.N. Synthesis, docking and in-vitro screening of mannich bases of thiosemicarbazide for anti-fungal activity. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2013.10.016 2 S.A. Pishawikar, H.N. More increased the numbers of profoundly and chronically immune Report of the Working, 1991; Silverman, 2004; Williams suppressed patients, who are susceptible to both serious inva- et al., 2007; Committee, 1997; Winstanley et al., 1994; Lennette sive and superficial fungal infections. The development of new et al., 1985). agents may provide additional options for the treatment of fungal infections and may help to overcome the limitations 2. Methods and materials of current treatments (Denning, 1991). By definition, mutual prodrugs are carrier-linked prodrugs Scheme of Synthesis:- consisting of two pharmacologically active agents coupled to- gether so that each acts as a promoiety for the other agent and vice versa. Individually mannich bases and thiosemicarbazide O O show varied pharmacological activities such as, anticancer, R2 + + NHHCl antimicrobial, antifungal, anticonvulsant, antimalarial, analge- R H R CH3 1 R sic and anti-inflammatory. Present work has used the concept 3 of mutual prodrug to synthesize mannich bases of thiosemicar- Aldehyde Secondary Amine Hydrochloride bazide as mutual prodrug and screening them as anti-fungal agents (Bhosle et al., 2006; Pandeya et al., 1999, 2003). Step 1 The mannich base is an end product in the mannich reaction, which is nucleophilic addition reaction of a non-enol- izable aldehyde and any primary or secondary amine to produce resonance stabilized imine (iminium ion or imine salt). O R1 In the synthesis of mannich bases, generally the use of R 3 HCl thiosemicarbazide is done as amine component, but the R N novelty of the present work is that, in step-1 successful synthe- R2 sis of a number of mannich bases was done using aldehyde, Mannich Base ketones and amines with aliphatic, aromatic, cyclic and hetero- cyclic nature. In step-2, synthesized mannich bases were con- densed with thiosemicarbazide to form mannich bases of S Step 2 thiosemicarbazide (Van de Kamp and Mosettig, 1936; March, H2N 1977; Waring, 1979; Mannich and Krosche, 1912; Thompson, NH NH2 1968). Thiosemicarbazide Computational methodologies have become a crucial component of many drug discovery programs, from hit identi- R2 fication to lead optimization. One key methodology is docking RN of small molecules to protein binding sites, pioneered during S R3 the early 1980s. The docking process involves the prediction N R1 of ligand conformation and orientation (or posing) within a H2N NH targeted binding site. The two aims of docking studies are Mannich Base of Thiosemicarbazide accurate structural modeling and correct prediction of activity. Docking studies have become a scientific approach for the study of macromolecular structures and interactions. Macro- molecular modeling by docking studies provides most detailed 2.1. Step-1 synthesis of mannich base possible view of drug–receptor interaction and has created a new rational approach to drug design, where the structure of Proportion of three reactants used for reactions was 1.00 drug is designed based on its fit to three dimensional structures molecular equivalent of carbonyl compound (ketone), of a receptor site. On the basis of docking scores one can pre- 1.05–1.10 molecular equivalent of amine in the form of dict the amount of activity that will be shown by compounds. hydrochloride salt and 1.5–2.0 molecular equivalent of To conform the mechanism of antifungal activity of synthe- aldehyde. sized compounds, docking of synthesized compounds was per- formed on the structure of Lanosterol 14 a-demethylase 2.2. Procedure (CYP51A1, P45014DM) an enzyme from cytochrome P450 family that catalyzes the oxidative removal of the 14a-methyl Amine was taken in a flat bottom flask and converted into group of lanosterol, an essential step in the production of hydrochloride salt using concentrated hydrochloric acid, for- sterols. Inhibition of this step leads to inhibition of synthesis mation of salt is confirmed by the use of Congo red paper. of ergosterol, a very essential component of fungal cell mem- To this were added ketone and aldehyde. The reaction mixture brane. For docking study Vlife MDS 3.5 was used (Lengauer was exposed to mechanical stirring. For some reactions heat- and Rarey, 1996; Kitchen et al., 2004). ing on water bath was done. The characterization of synthesized compounds was done Optimization of reaction conditions with respect to time by IR and H NMR. The compounds were screened for and temperature was done on individual basis for each reac- antifungal activity using Brain heart infusion (BHI) broth dilu- tion. Time required varied from 30 min to 12–14 h, with tem- tion method using Candida albicans (ATCC Code 10231), perature conditions varying from room temperature with Apergillus niger. (ATCC Code 16404) and using concentration mechanical stirring, to heating on water bath at temperature of Fluconazloe (30 lg/ml) as standard drug (Andrews, 2001; Please cite this article in press as: Pishawikar, S.A., More, H.N. Synthesis, docking and in-vitro screening of mannich bases of thiosemicarbazide for anti-fungal activity. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2013.10.016 Synthesis, docking and in-vitro screening of mannich bases of thiosemicarbazide for anti-fungal activity 3 Table 1 Synthesized compounds R2 RN S R3 N R1 H2N NH Mannich Base of Thiosemicarbazi . Sr. No. Code R R1 R2 R3 01 K1 CH3 HC2H5 C2H5 02 K2 CH3 HCH3 CH3 03 K3 CH3 CH3CH2 CH3CH2CH2 CH3CH2CH2 04 K4 CH3CH2 CH3CH2CH2 CH2CH2OH CH2CH2OH 05 K5 CH3CH2CH2 CH3–CH–CH3 CH3CH2CH2CH2 CH3CH2CH2CH2 06 K6 CH3CH2 CH3CH2CH2 CH3CH2CH2 O 07 K7 C2H5 C2H5 O Cl 08 K8 CH3 CH3CH2CH2 CH3CH2CH2 09 K9 CH3 CH3CH2CH2 CH3CH2CH2 O 10 K10 CH3 CH3CH2CH2 CH3CH2CH2 O 11 K11 CH3CH2CH2 CH2CH2OH CH2CH2OH O H3C 12 K12 CH3CH2 C2H5 C2H5 O 13 K13 O N HC2H5 C2H5 2 14 K14 HC2H5 C2H5 15 K15 O HC2H5 C2H5 16 K16 CH3 C2H5 C2H5 Cl 17 K17 HC2H5 C2H5 Cl O Please cite this article in press as: Pishawikar, S.A., More, H.N. Synthesis, docking and in-vitro screening of mannich bases of thiosemicarbazide for anti-fungal activity. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2013.10.016 4 S.A. Pishawikar, H.N. More Table 1 (continued) Sr. No. Code R R1 R2 R3 18 K18 CH3 H O N 19 K19 CH3CH2CH2 H O N 20 K20 H O N 21 K21 O H O N 22 K22 CH3 Cl O N 23 K23 CH3 O O N 24 K24 H O O N 25 K25 H CH CH O N Table 2 Physicochemical data of synthesized compounds. Code of compound Color Solubility M.P.
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