MM Matin et al. Medical Research Archives vol 8 issue 7. Medical Research Archives RESEARCH ARTICLE 2e`1 PASS Predication, Antiviral, in vitro Antimicrobial, and ADMET Studies of Rhamnopyranoside Esters Authors Mohammed M Matin1, Mohammad HO Roshid2, Sreebash C Bhattacharjee3 and Abul KMS Azad4 Affiliations 1 Bioorganic & Medicinal Chemistry Laboratory, Department of Chemistry, University of Chittagong, Chattogram-4331, Bangladesh 2 Department of Anaesthesia and Intensive Care Medicine, Chattogram Medical College, Chattogram- 4203, Bangladesh 3 Chemical Research Division, Bangladesh Council of Scientific & Industrial Research (BCSIR) Laboratories, Chattogram-4220, Bangladesh 4 Department of Chemistry, Chattogram Govt. College, Chattogram-4203, Bangladesh Corresponding Author: MM Matin E-mail address: [email protected] Tel.: +88 01716 839689. Abstract Sugar derived esters (SEs) with potential antimicrobial activity were found to be a better choice to solve the multidrug resistant (MDR) pathogens due to improved antimicrobial efficacy, biodegradability, non-toxic, and non-allergic properties. In this context, a series of benzyl -L- rhamnopyranoside esters with different chain length (C2-C18) were employed for PASS predication, antiviral, and in vitro antimicrobial activity test. The in vitro antimicrobial tests against four bacterial, and four fungal pathogens along with PASS predication indicated that these sugar esters acted as better antifungals as compared to antibacterial functionality. The study revealed that the incorporation of octanoyl (C8) and lauroyl (C12) group(s) at C-3 position of rhamnopyranoside possessed promising antimicrobial, and anti-carcinogenic potentiality with good pharmacokinetic (pkCSM), and drug likeness properties. Also, attachment of multiple ester groups enhanced various drug likeness, and medicinal chemistry friendliness conditions. Overall, the present findings might be useful for the development of rhamnopyranoside based novel MDR antimicrobial drugs. Keywords: Benzyl -L-rhamnopyranoside; Sugar esters (SEs); PASS predication; Antiviral; Antimicrobial activities; ADMET. Copyright 2020 KEI Journals. All Rights Reserved MM Matin et al. Medical Research Archives vol 8 issue 7. July 2020 Page 2 of 13 1. Introduction composed of a hydrophilic carbohydrate Antimicrobial infections causes serious moiety, and one or more fatty acids as health problem worldwide. In this respect lipophilic moieties.5 SEs have attracted many natural and synthetic antibacterial considerable research interest and wide drugs (penicillin, daptomycin, tigecycline, range of application in industry, and linezolid etc.), and antifungal drugs medicine mainly due to their considerable (amphotericin B, nystatin, flucytosine, insecticidal, and antimicrobial activities.6-7 papulacandins, azoles, echinocandin etc.) Of the SEs, rhamnopyranoside derived are in clinical use.1 Different carbohydrate esters are found to be of great importance as (sugar) residues are found in many naturally antigenic, anticarcinogenic,8 antimicrobial,9- occurring different antimicrobial drugs like 10 and pharmacological properties. For papulacandins, mannosylated nystatin example, 2-O-acetyl-3,4-di-O-(E)-p-metho- (nystatin A1), and polyenes.2 Generally, xycinnamoyl--L-rhamnopyranoside(s) (1; addition of sugar moieties in these drugs Figure 1) isolated from S. buergeriana (nystatin A1, and amphotericin B) led to exerted significant protective effects against higher solubility and reduced hemolytic glutamate-induced neurodegeneration in toxicity although biological activities of primary cultures of cortical neurons.11 Very these polyene antifungals depend on the recently, four new rhamnopyranose esters number and type of extended second sugar (e.g. 2a-d) were isolated from the stem of P. residue.3 odorata and found to be good scaffolds for Due to the highly specific interactions with developing new anti-breast cancer and physiological receptors carbohydrates antioxidant compounds.12 All the participate in many crucial biological observations indicated that esterification of processes. Their esters, especially the rhamnose moiety in these natural monosaccharide based sugar esters (SEs), products is essential for high affinity binding are involved in many diverse biological and selectivity as well as for the events in organisms from all kind of life.4 development of anticancer agents (RSK They are generally biodegradable, non-toxic, inhibitors).8,12 non-allergic, and non-irritating as are Figure 1. Naturally found bioactive rhamnopyranoside esters 1 and 2a-d. Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra MM Matin et al. Medical Research Archives vol 8 issue 7. July 2020 Page 3 of 13 Emergence of multiple drug resistant 2. Materials and methods (MDR) pathogenic bacteria and fungi is a 2.1. Materials: rhamnopyranoside esters global concern in addition to numerous 4-20 obstacles encountered on delivery to the site In the present study, seventeen esters with of microbial infection. To combat with these different side chain length and different MDR organisms there is urgent need for groups 4-20 of benzyl -L- establishment of new chemotherapeutic rhamnopyranoside (3) were used as test agents with novel mode of action. In this chemicals. These compounds (mainly 3-O- respect as well as our continuous effort to acyl esters), as shown in Figure 2, were find novel antimicrobial SEs,13-16 we report synthesized from 3 by dibutyltin oxide herein the antimicrobial efficacy of several method followed by direct method and well rhamnopyranoside esters against four characterized by Kabir and Matin.17-18 For pathogenic bacterial and four fungal strains better comparison, standard antibacterial along with ADMET. antibiotic tetracycline and antifungal antibiotic fluconazole were used. Figure 2. Rhamnopyranoside based SEs 4-20 as antimicrobials. 2.2. PASS predication possible for a particular compound. Being Initially, structures of the compounds were probabilities, the Pa and Pi values vary from drawn and then converted into their SD file 0.000 to 1.000 and in general, Pa+Pi≠1, format and used to predict biological since these probabilities are calculated spectrum using PASS online version. Web independently. The PASS prediction results based PASS (prediction of activity spectra were interpreted and used in a flexible for substances; http://www.pharmaexpert.ru/ manner, such as (i) when Pa>0.7, the chance PASSonline/index.php) was used for the to find the activity experimentally is high, prediction of biological spectrum of these (ii) if 0.5<Pa<0.7, the chance to find the SEs.9 This program is designed to anticipate activity experimentally is less, but the a plethora of biological activities with 90% compound is probably not so similar to accuracy. PASS result is designated as Pa known pharmaceutical agents, and (iii) if (probability for active compound) and Pi Pa<0.5, the chance to find the activity (probability for inactive compound). Only experimentally is less, but the chance to find activities with Pa>Pi are considered as a structurally. Hence, the predicted activity Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra MM Matin et al. Medical Research Archives vol 8 issue 7. July 2020 Page 4 of 13 of spectrum is known as the intrinsic at 24 h intervals for two days. The activity property of the compound. was expressed in terms of inhibition zone diameter in mm and each experiment was 2.3. Antiviral activities evaluation carried out three times. Tetracycline Antiviral compounds (AVCs) are a special (antibiotic used for bacterial infections, category of antimicrobial drugs used for brand name Tetrax-500, from Square treating viral infections by inhibiting the Pharmaceuticals Ltd., Bangladesh) was used development of the viral pathogen(s) inside as a positive control and compared with the host cell. For antiviral activity tested chemicals under identical conditions. predication, we used online software The in vitro antifungal efficacy was (http://crdd.osdd.net/servers/avcpred) which investigated based on food poisoning showed percentage of inhibition.19 SD file technique23-24 against four human format of the compounds were used for pathogenic fungi viz. Aspergillus flavus, predications. The evaluation conducted for Aspergillus niger, Aspergillus fumigatus and the antiviral therapeutics development and Penicillium notatum. Sabouraud (agar and also in identifying the best inhibitory broth, PDA) medium was used for culture of compounds for further research. fungi. Necessary amount of medium was taken in a conical flask separately and was 2.4. In vitro antimicrobial activities sterilized in autoclave (at 121 ºC and 15 psi) evaluation for 15 minutes. After autoclaving, weighed Two Gram-positive bacteria (Bacillus cereus amount of test chemical (2%) was added to BTCC 19, Bacillus megaterium ATCC the sterilized medium in conical flask at the 6633) and two Gram-negative bacteria point of pouring to obtain desired (Escherichia coli ATCC 25922, concentration. The flask was shaken Pseudomonas aeruginosa CRL, ICDDR,B) thoroughly to mix the chemical with the were used for in vitro antibacterial activity medium homogeneously before pouring. test using the disc diffusion method.20-22 The medium with definite concentration Dimethylformamide (DMF) was used as a (2%) of chemical was poured at the rate of solvent, and control for the test chemicals, 100 μL in sterilized glass petri dishes and a 2% solution of each compound