title: Development of antibacterial conjugates using sulfamethoxazole with monocyclic terpenes: A systematic medicinal chemistry based computational approach.
abstract: OBJECTIVE
  To develop 6 conjugate agents of the moribund antibiotic sulfamethoxazole (SMZ) joined to 6 individual monoterpenes, followed by protocols of medicinal chemistry as potent antibacterials, against multidrug resistant (MDR) human gruesome pathogenic bacteria.
  
  
  METHODS
  Antibacterial activities of the proposed conjugates were ascertained by the 'prediction of activity spectra of substances' (PASS) program. Drug-likeness parameters and toxicity profiles of conjugates were standardized with the Lipinski rule of five, using cheminformatic tools, Molsoft, molinspiration, OSIRIS and ProTox. Antibacterial activities of individual chemicals and conjugates were examined by targeting the bacterial folic acid biosynthesis enzyme, dihydropteroate synthases (DHPSs) of bacteria, Bacillus anthracis, Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae and Mycobacterium tuberculosis, with 3D structures of DHPSs from protein data bank.
  
  
  RESULTS
  According to the PASS program, biological spectral values of conjugate-2, conjugate-5 and conjugate-6 were ascertained effective with 'probably active' or 'Pa' value > 0.5, for anti-infective and antituberculosic activities. Using molecular docking against 5 cited bacterial DHPSs, effective docking scores of 6 monoterpenes in the specified decreasing order (kcal/mol): -9.72 (eugenol against B. anthracis), -9.61 (eugenol against S. pneumoniae), -9. 42 (safrol, against B. anthracis), -9.39 (thymol, against M. tuberculosis), -9.34 (myristicin, against S. pneumoniae) and -9.29 (thymol, against B. anthracis); whereas the lowest docking score of SMZ was -8.46kcal/mol against S. aureus DHPS. Similarly, effective docking scores of conjugates were as specified (kcal/mol.): -10.80 (conjugate-4 consisting SMZ+safrol, against M. tuberculosis), -10.78 (conjugate-5 consisting SMZ+thymol, against M. tuberculosis), -10.60 (conjugate-5 against B. anthracis), -10.26 (conjugate-2 consisting SMZ+ eugenol, against M. tuberculosis), -10.25 (conjugate-5, against S. aureus) and -10.19 (conjugate-2 against S. pneumoniae. Conjugates-2 and -5 were the most effective antibacterials based on Lipinski rule of five with lethal doses 3471 and 3500mg/kg, respectively and toxicity class levels.
  
  
  CONCLUSIONS
  Conjugate-2 and conjugate-5 were more effective than individual monoterpenes and SMZ, against pathogenic bacteria. Synthesis, characterization and in vitro antibacterial study with acute toxicity testing for Wister rat model of the conjugate-5 could land at success in the recorded computational trial and it could be promoted for synthesis in the control of MDR bacteria.
authors.affiliation: Central Research Laboratory, IMS and Sum Hospital, Siksha 'O' Anusandhan University, K-8 Kalinga Nagar, Bhubaneswar 751003, Odisha, India.
authors.forename: Shasank S
authors.initials: SS
authors.lastname: Swain
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Siksha 'O'Anusandhan University, Bhubaneswar 751003, Odisha, India.
authors.forename: Sudhir K
authors.initials: SK
authors.lastname: Paidesetty
authors.affiliation: Central Research Laboratory, IMS and Sum Hospital, Siksha 'O' Anusandhan University, K-8 Kalinga Nagar, Bhubaneswar 751003, Odisha, India. Electronic address: rnpadhy54@gmail.com.
authors.forename: Rabindra N
authors.initials: RN
authors.lastname: Padhy
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D004094:Dihydropteroate Synthase / Q000737:chemistry; D024901:Drug Resistance, Multiple, Bacterial; D008826:Microbial Sensitivity Tests; D017386:Sequence Homology, Amino Acid; D013420:Sulfamethoxazole / Q000737:chemistry* / Q000494:pharmacology; D013729:Terpenes / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D013729:Terpenes; D004094:Dihydropteroate Synthase; D013420:Sulfamethoxazole
keywords: Dihydropteroate synthase; Molecular docking; Monoterpene conjugates; PASS prediction; Sulfamethoxazole; Toxicity assessment