Abstract
Leprosy continues to be the belligerent public health hazard for the causation of high disability and eventual morbidity cases with stable prevalence rates, even with treatment by the on-going multidrug therapy (MDT). Today, dapsone (DDS) resistance has led to fear of leprosy in more unfortunate people of certain developing countries. Herein, DDS was chemically conjugated with five phytochemicals independently as dapsone-phytochemical conjugates (DPCs) based on azo-coupling reaction. Possible biological activities were verified with computational chemistry and quantum mechanics by molecular dynamics simulation program before chemical synthesis and spectral characterizations viz., proton-HNMR, FTIR, UV and LC-MS. The in vivo antileprosy activity was monitored using the ‘mouse-foot-pad propagation method’, with WHO recommended concentration 0.01% mg/kg each DPC for 12 weeks, and the host-toxicity testing of the active DPC4 was seen in cultured-human-lymphocytes in vitro. One-log bacilli cells in DDS-resistant infected mice footpads decreased by the DPC4, and no bacilli were found in the DDS-sensitive mice hind pads. Additionally, the in vitro host toxicity study also confirmed that the DCP4 up to 5,000 mg/L level was safety for oral administration, since a minor number of dead cells were found in red color under a fluorescent microscope. Several advanced bioinformatics tools could help locate the potential chemical entity, thereby reducing the time and resources required for in vitro and in vitro tests. DPC4 could be used in place of DDS in MDT, evidenced from in vivo antileprosy activity and in vitro host toxicity study.
Highlights
Multidrug therapy (MDT) with the sulphonamide drug, dapsone (4, 4′-diamino diphenyl sulfone or, DDS), along with antibiotics, rifampicin, clofazimine, and ofloxacin is the ongoing treatment option for leprosy, recommended by World Health Organization (WHO) today[1,2,3,4]
Www.nature.com/scientificreports bacterial precursor para-aminobenzoic acid, which competitively inhibits the biosynthesis of bacterial folic acid, by targeting the putative Dihydropteroate synthase (DHPS) enzyme[9,10]
Antileprosy activities of synthesized conjugates were tested in ‘mouse-foot-pad propagation’ (MFP) method using both DDS sensitive and resistant strains after inducing the disease by infecting mice; and the active most conjugate was selected for toxicity study using cultured human lymphocytes in vitro, isolated from umbilical cord blood (UCB)
Summary
Multidrug therapy (MDT) with the sulphonamide drug, dapsone (4, 4′-diamino diphenyl sulfone or, DDS), along with antibiotics, rifampicin, clofazimine, and ofloxacin is the ongoing treatment option for leprosy, recommended by World Health Organization (WHO) today[1,2,3,4]. Continuing with wild-type (Wt) and mutant-types (Mt) forms of MlDHPS as the identified targets[15], the development of chemically altered DDS inhibiting bacterial folic acid synthesis had been organised[1]. The antileprosy efficacy and drug-likeness characteristics of proposed DDS-phytochemical conjugates (DPCs) were screened through chemoinformatics- and structural bioinformatics-tools viz., prediction of activity spectra for substances (PASS), molecular docking and molecular dynamic (MD) simulations with possible toxicity profile prediction in an ideal drug development approach, before the direct synthesis of conjugates. Antileprosy activities of synthesized conjugates were tested in ‘mouse-foot-pad propagation’ (MFP) method using both DDS sensitive and resistant strains after inducing the disease by infecting mice; and the active most conjugate was selected for toxicity study using cultured human lymphocytes in vitro, isolated from umbilical cord blood (UCB)
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