br Experimental All starting materials and reagents were pur

Experimental All starting materials and reagents were purchased from Sigma-Aldrich, Merck and Loba Chemie. Thin layer chromatography (TLC) was performed on silica gel G60 F254 (Merck) plates and eluted with the mobile phase n-hexane: ethyl acetate (70:30%v/v). Melting points were recorded on automated melting point system and are uncorrected. IR spectra were obtained on a Thermo Scientific, Nicolet 6700 spectrophotometer using KBr pellet disk method. NMR spectra were documented on Bruker 400MHz using DMSO-d6 as solvent and TMS as an internal standard. Chemical shifts are reported in parts per million (δ in ppm). Mass spectra were recorded on Waters Micromass Q-Tof Micro. Elemental analysis was performed on the Thermo Scientific Flash 2000.
Results and discussion
Conclusion Analogues of benzothiazole have been synthesized and characterized. To avoid late stage failure, it is important to study the preliminary pharmacokinetic parameters. The results of in silico pharmacokinetic data suggested that all the molecules might be considered as drug. So in vitro antimicrobial, cytotoxicity and genotoxicity on S. pombe cells and antimalarial on P. falciparum strain of these analogues were investigated. It was found that the antibacterial activity could be correlated to energies of the LUMO and maximum LUMO electron density derived from DFT and PM6 calculations. All the compounds possessed moderate to good inhibitory potency against bacterial strains and did not show any antifungal activities. The compounds J 5, J 6 and J 8-J 10 were found to possess maximum toxicity against S. pombe cells at cellular level. All the compounds J 1-J 10 showed smearing type pattern on agarose gel due to toxic nature of these compounds. The compounds J 1, J 2, J 3, J 5 and J 6 where substituent is attached to phenyl ring were found to be most potent against P. falciparum strain. The in silico molecular docking study of these active compounds were performed and all the compounds showed good interaction with the KPT-185 of Pf-DHFR with great ease. The antimalarial efficacy was further proved by in vitro DHFR enzyme inhibition study. All the compounds showed potent DHFR inhibitory activity with IC50 in the range of 0.0312–0.0531µM. This study could identify new antibacterial and antimalarial agents which could be used as lead molecules for further research and development of antibacterial and antimalarial agents.
Acknowledgement The authors thank the authorities of Charotar University of Science & Technology (CHARUSAT), Changa, Gujarat, India for providing the facilities to carry out this investigation. They also thank Dr. Devendra Tiwari, School of Chemistry, University of Bristol, United Kingdom. for his help in molecular orbital study. Mr. Parth Thakor is thankful to DST INSPIRE program for the fellowship.
Introduction Mammalian cells cannot synthesize folates de novo and are dependent on a supply of fully reduced folates to drive a series of 1-carbon reactions. Folates are hydrophilic anionic molecules that do not cross biological membranes by diffusion. The best-characterized folate transporter is the ubiquitously expressed reduced folate carrier (RFC) [25]. Importantly, in addition to its role in transporting folates, RFC is a major transporter of antifolate drugs used for cancer chemotherapy, such as MTX [24]. Intracellular folates are predominantly long-chain polyglutamate derivatives. Inside the cell, folylpolyglutamate synthetase (FPGS) adds glutamate molecules to folate, which is important for the retention of folates in cells [57]. The same mechanism is involved in MTX conversion to active methotrexate polyglutamates (MTXPGs) by FPGS [47]. Catabolism of MTXPGs is dependent on the rate of entry of polyglutamates into lysosomes and hydrolysis by the lysosomal enzyme gamma-glutamyl hydrolase. Effective intracellular levels of MTX are reduced by various transport mechanisms, including ABC transporters such as ABCB1, ABCG2 [46] and many others [20].