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Fulltext Neuroprotective potential of ocimum sanctum (Linn) leaf extract in preventing and attenuating stress induced substantia nigral neuronal damage in rats

Rodrigues V, Rao MS, Rao GS, Rao K G M

J Ayurveda Integr Med, 2022;13(4):100651.
PMID: 36370484 DOI: 10.1016/j.jaim.2022.100651

BACKGROUND: In Ayurveda; an Indian system of traditional medicine, Ocimum sanctum is said to have remedial effect on hriddaurbalya (problems affecting the mind), aakshepayukta vikara (nervous disorders) and shiroroga (diseases of head). Hence, in Ayurvedic practice, it is profoundly used as an antistress medicine. Stress is known to affect neurons of functionally significant brain regions like substantia nigra. However, experimental evidence showing its effect on morphology of substantia nigral neurons is lacking. In addition, whether the O. sanctum treatment attenuates stress induced substantia nigral neuronal structural changes is not known.
OBJECTIVES: To know the effect of stress on morphology of substantia nigral neurons and the effect of O. sanctum fresh leaf extract (OSE) on substantia nigral neurons of stressed rats.
MATERIAL AND METHODS: Present study included three experiments. Experiment I: To study the effect of 3 and 6 weeks of foot shock stress in rats; Experiment II- To study the effect of 3 weeks of OSE treatment on 3 week-stress undergoing rats and on 3 week-stressed rats; Experiment III- To study the effect of 6 weeks of OSE treatment in 6 week-stress undergoing rats and in 6 week-stressed rats.
RESULTS: In experiment I, stress had significant deleterious effect on dendritic arborization of substantia nigral neurons. Experiments II and III showed prevention and attenuation of the stress induced dendritic atrophy of substantia nigral neurons in both 2 ml and 4 ml OSE treatment groups. Protective effect of OSE was more pronounced in rats which are treated for a longer duration.
CONCLUSIONS: Foot shock stress induces neuronal damage in the substantia nigra of rats. Treatment with fresh leaf extract of O. sanctum could prevent and attenuate the foot shock stress induced behavioral deficit and substantia nigral neuronal damage.
A midlecture student seminar: an activity to break the monotony

Mohandas Rao KG

Adv Physiol Educ, 2006 Dec;30(4):262-263.
PMID: 17108258
An additional muscle in the back of the leg

Rao KG, Bhat MS

Clin Anat, 2006 Nov;19(8):724-5.
PMID: 16944500
Centella asiatica (L.) leaf extract treatment during the growth spurt period enhances hippocampal CA3 neuronal dendritic arborization in rats

Mohandas Rao KG, Muddanna Rao S, Gurumadhva Rao S

Evid Based Complement Alternat Med, 2006 Sep;3(3):349-57.
PMID: 16951719

Centella asiatica (CeA) is a creeping plant growing in damp places in India and other Asian countries. The leaves of CeA are used for memory enhancement in the Ayurvedic system of medicine, an alternative system of medicine in India. In this study, we have investigated the effect during the rat growth spurt period of CeA fresh leaf extract treatment on the dendritic morphology of hippocampal CA3 neurons, one of the regions of the brain concerned with learning and memory. Neonatal rat pups (7 days old) were fed with 2, 4 or 6 ml kg(-1) body weight of fresh leaf extract of CeA for 2, 4 or 6 weeks. After the treatment period the rats were killed, their brains were removed and the hippocampal neurons were impregnated with silver nitrate (Golgi staining). Hippocampal CA3 neurons were traced using a camera lucida, and dendritic branching points (a measure of dendritic arborization) and intersections (a measure of dendritic length) were quantified. These data were compared with data for age-matched control rats. The results showed a significant increase in the dendritic length (intersections) and dendritic branching points along the length of both apical and basal dendrites in rats treated with 4 and 6 ml kg(-1) body weight per day of CeA for longer periods of time (i.e. 4 and 6 weeks). We conclude that the constituents/active principles present in CeA fresh leaf extract have a neuronal dendritic growth stimulating property; hence, the extract can be used for enhancing neuronal dendrites in stress and neurodegenerative and memory disorders.
Variant origin of an arterial trunk from axillary artery continuing as profunda brachii artery--a unique arterial variation in the axilla and its clinical implications

Naveen K, Jyothsna P, Nayak SB, Mohandas RK, Swamy RS, Deepthinath R, et al.

Ethiop J Health Sci, 2014 Jan;24(1):93-6.
PMID: 24591805

BACKGROUND: Axillary artery is known to show different variations mostly in its branching pattern. Similarly, the origin of profunda brachii is often encountered with abnormality. Therefore, when the vascular variations in the upper limb persist, mostly it is confined to its branching pattern followed by its variant origin. But, among all the reported variations of profunda brachii, its variant origin from the 3rd part of the axillary artery with common trunk for the branches of axillary artery is unique.
CASE DETAILS: We report here an anomalous origin of profunda brachii as continuation of an arterial trunk arising from 3rd part of the axillary artery. This common trunk at its commencement passed between 2 roots of median nerve and gave branches of 3rd part of axillary artery before it continued as profunda brachii artery. The further course and branching pattern of profunda brachii were normal.
CONCLUSION: Since the axillary artery is next choice of artery for arterial cannulation in cardiopulmonary bypass procedures, prior knowledge of existence of such variation in its branching pattern helps in avoiding possible diagnostic or interventional therapeutic errors.
Toxicity of xylene in occupationally exposed workers: A high-performance liquid chromatography analysis

Rajan ST, Narasimhan M, Rao KB, Jacob TE

J Oral Maxillofac Pathol, 2019 9 14;23(2):303.
PMID: 31516245 DOI: 10.4103/jomfp.JOMFP_297_18

Background: Xylene is one of the most commonly used solvents in industrial and medical technologies. Several health hazards of xylene have been documented in literature. Workers in certain forces appear to have the greatest potential for exposure to high concentrations of xylene - histopathology technicians and painters are two such groups. This study was undertaken with the aim to determine the level of xylene exposure and the various systemic health effects among these groups.
Methodology: The study was performed by analyzing the urine samples of the participants for methylhippuric acid, the established biomarker of xylene with the aid of high-performance liquid chromatography.
Results and Conclusion: The work hours per week of the occupationally exposed participants were statistically analyzed with that of the excretory values of the metabolites of xylene, and the P value was found to be highly significant. Various side effects of xylene including respiratory, dermatological, neurological and gastrointestinal symptoms were observed among the study groups.
The morphological and microscopical characteristics of posterior layer of human thoracolumbar fascia; A potential source of low back pain

Marpalli S, Mohandas Rao KG, Venkatesan P, George BM

Morphologie, 2021 Feb 09.
PMID: 33579637 DOI: 10.1016/j.morpho.2021.01.001

BACKGROUND: Posterior layer of thoracolumbar fascia (PTLF) is the deep fascia of back of the trunk, which connects the trunk, upper limb and lower limb muscles. Very few cadaveric studies of posterior layer of thoracolumbar fascia (PTLF) are found in the literature, which mention the presence of nerve receptors in it but, quantification of the nerve receptors where not found. Providing the morphological and morphometrical data of PTLF may help the exercise physiologists, sports physicians, occupational health assistants and, physiotherapists to modify or invent new protocol of treatment to help the society.
METHODS: In this study, twenty formalin embalmed human cadavers were used and we have documented the orientation of the PTLF and quantified the number of peripheral nerve endings at the different vertebral levels.
RESULTS: Mean distance of PTLF from vertebral spines to the musculofascial junction was at thoracic region 3.38cm and 3.34cm; at lumbar region, it was 7.4cm and 7.36cm and at sacral region it was 2.98cm and 2.96cm on right and left side, respectively. The angulation of PTLF varies from 18-110 degrees at different vertebral levels. The microscopic data shows the thickness of PTLF and number of nerve endings in the sacral level is increased compared to that of thoracic vertebral levels.
CONCLUSIONS: We have contributed the novel morphological and microscopical details to the limited existing data on PTLF. We also have provided the quantitative data of nerve fibers, which are possible nociceptors of PTLF.
Evaluation of amygdaloid neuronal dendritic arborization enhancing effect of Centella asiatica (Linn) fresh leaf extract in adult rats

Mohandas Rao KG, Rao MS, Rao GS

Chin J Integr Med, 2012 Dec 03.
PMID: 23212568

OBJECTIVE: Centella asiatica (CeA), a creeper, growing in moist places in India and other Asian countries. Leaves of CeA are used for memory enhancement in Ayurvedic system of medicine, an alternative system of medicine originated from India. In the present study, we have investigated the role of CeA fresh leaf extract treatment on adult rats on dendritic morphology of amygdaloid neurons, one of the regions concerned with learning and memory. METHODS: Adult rats (2.5-month old) were fed with 2, 4 and 6 mL/(day kg) of fresh leaf extract of CeA for 2, 4 and 6 weeks. After the treatment period the rats were killed, brains were removed and amygdaloid neurons were impregnated with silver nitrate (Golgi staining). Such silver impregnated amygdaloid neurons were traced using camera lucida and dendritic branching points (a measure of dendritic arborization) and intersections (a measure of dendritic length) were quantified. These data were compared with those of age matched control rats. RESULTS: The results showed a significant increase in the dendritic length (intersections) and dendritic branching points in amygdaloid neurons of the rats treated with higher dose [6 mL/(day·kg)] of CeA for longer period of time (i.e. 6 weeks). CONCLUSIONS: Constituents/active principles present CeA fresh leaf extract has neuronal dendritic growth stimulating property; hence it can be used for enhancing neuronal dendrites in stress and other neurodegenerative and memory disorders.
Fulltext Establishing links between assessments and expected learning outcomes through curriculum mapping in a dental physiology curriculum

Vashe A, Devi V, Rao KR, Abraham RR

Natl Med J India, 2021 8 17;34(1):40-45.
PMID: 34397005 DOI: 10.4103/0970-258X.323445

Background: . The relevance of curriculum mapping to determine the links between expected learning outcomes and assessment is well stated in the literature. Nevertheless, studies confirming the usage of such maps are minimal.
Methods: . We assessed links through curriculum mapping, between assessments and expected learning outcomes of dental physiology curriculum of three batches of students (2012-14) at Melaka-Manipal Medical College (MMMC), Manipal. The questions asked under each assessment method were mapped to the respective expected learning outcomes, and students' scores in different assessments in physiology were gathered. Students' (n = 220) and teachers' (n=15) perspectives were collected through focus group discussion sessions and questionnaire surveys.
Results: . More than 75% of students were successful (≥50% scores) in majority of the assessments. There was moderate (r=0.4-0.6) to strong positive correlation (r=0.7-0.9) between majority of the assessments. However, students' scores in viva voce had a weak positive correlation with the practical examination score (r=0.230). The score in the assessments of problem-based learning had either weak (r=0.1-0.3) or no correlation with other assessment scores.
Conclusions: . Through curriculum mapping, we were able to establish links between assessments and expected learning outcomes. We observed that, in the assessment system followed at MMMC, all expected learning outcomes were not given equal weightage in the examinations. Moreover, there was no direct assessment of self-directed learning skills. Our study also showed that assessment has supported students in achieving the expected learning outcomes as evidenced by the qualitative and quantitative data.
A fatal case of primary melioidotic prostatic abscess: the peril of poor drug compliance

Wahab AA, Norliyana N, Ding CH, Nurzam SCH, Salbiah N, Rao KR

Trop Biomed, 2020 Sep 01;37(3):560-565.
PMID: 33612771 DOI: 10.47665/tb.37.3.560

Primary prostatic melioidosis is a rare presentation of melioidosis even in melioidosis endemic areas. We report a case of a 58-year-old man with underlying diabetes mellitus who presented with a 5-day history of high-grade fever associated with lower urinary tract symptoms. Suprapubic tenderness and tender prostatomegaly were noted on examination. An abdominal computed tomography (CT) scan confirmed the presence of a prostatic abscess. Both blood and prostatic pus cultures grew Burkholderia pseudomallei. He was initially started on intravenous ceftazidime, followed by an escalation to intravenous meropenem. He was discharged home with oral amoxicillin-clavulanate and doxycycline after completing 12 days of meropenem. Unfortunately, his compliance to oral antibiotic therapy was poor, and he succumbed to the disease.
Fulltext Turnovers of Sex-Determining Mutation in the Golden Pompano and Related Species Provide Insights into Microevolution of Undifferentiated Sex Chromosome

Guo L, Malara D, Battaglia P, Waiho K, Davis DA, Deng Y, et al.

Genome Biol Evol, 2024 Mar 02;16(3).
PMID: 38408866 DOI: 10.1093/gbe/evae037

The suppression of recombination is considered a hallmark of sex chromosome evolution. However, previous research has identified undifferentiated sex chromosomes and sex determination by single SNP in the greater amberjack (Seriola dumerili). We observed the same phenomena in the golden pompano (Trachinotus ovatus) of the same family Carangidae and discovered a different sex-determining SNP within the same gene Hsd17b1. We propose an evolutionary model elucidating the turnover of sex-determining mutations by highlighting the contrasting dynamics between purifying selection, responsible for maintaining W-linked Hsd17b1, and neutral evolution, which drives Z-linked Hsd17b1. Additionally, sporadic loss-of-function mutations in W-linked Hsd17b1 contribute to the conversion of W chromosomes into Z chromosomes. This model was directly supported by simulations, closely related species, and indirectly by zebrafish mutants. These findings shed new light on the early stages of sex chromosome evolution.
Fulltext Antimicrobial activities of green synthesized gums-stabilized nanoparticles loaded with flavonoids

Anwar A, Masri A, Rao K, Rajendran K, Khan NA, Shah MR, et al.

Sci Rep, 2019 02 28;9(1):3122.
PMID: 30816269 DOI: 10.1038/s41598-019-39528-0

Herein, we report green synthesized nanoparticles based on stabilization by plant gums, loaded with citrus fruits flavonoids Hesperidin (HDN) and Naringin (NRG) as novel antimicrobial agents against brain-eating amoebae and multi-drug resistant bacteria. Nanoparticles were thoroughly characterized by using zetasizer, zeta potential, atomic force microscopy, ultravoilet-visible and Fourier transform-infrared spectroscopic techniques. The size of these spherical nanoparticles was found to be in the range of 100-225 nm. The antiamoebic effects of these green synthesized Silver and Gold nanoparticles loaded with HDN and NRG were tested against Acanthamoeba castellanii and Naegleria fowleri, while antibacterial effects were evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and neuropathogenic Escherichia coli K1. Amoebicidal assays revealed that HDN loaded Silver nanoparticles stabilized by gum acacia (GA-AgNPs-HDN) quantitatively abolished amoeba viability by 100%, while NRG loaded Gold nanoparticles stabilized by gum tragacanth (GT-AuNPs-NRG) significantly reduced the viability of A. castellanii and N. fowleri at 50 µg per mL. Furthermore, these nanoparticles inhibited the encystation and excystation by more than 85%, as well as GA-AgNPs-HDN only completely obliterated amoeba-mediated host cells cytopathogenicity. Whereas, GA-AgNPs-HDN exhibited significant bactericidal effects against MRSA and E. coli K1 and reduced bacterial-mediated host cells cytotoxicity. Notably, when tested against human cells, these nanoparticles showed minimal (23%) cytotoxicity at even higher concentration of 100 µg per mL as compared to 50 µg per mL used for antimicrobial assays. Hence, these novel nanoparticles formulations hold potential as therapeutic agents against infections caused by brain-eating amoebae, as well as multi-drug resistant bacteria, and recommend a step forward in drug development.
Synthesis, in vitro antimycobacterial evaluation and docking studies of some new 5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one schiff bases

Narender M, Jaswanth S B, Umasankar K, Malathi J, Raghuram Reddy A, Umadevi KR, et al.

Bioorg Med Chem Lett, 2016 Feb 01;26(3):836-840.
PMID: 26755393 DOI: 10.1016/j.bmcl.2015.12.083

Development of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) has been considered as major health burden, globally. In order to develop novel, potential molecules against drug resistant TB, twenty two (22) new 3-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7-benzyl-2-methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were designed and synthesized by using appropriate synthetic protocols. Pantothenate synthetase (PS) was considered as the target for the molecular docking studies and evaluated the binding pattern at active site, as PS plays a significant role in the biosynthesis of pantothenate in Mycobacterium tuberculosis (MTB). The preliminary in vitro antibacterial screening of test compounds was carried out against two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria. The antimycobacterial screening was performed against MTB H37Rv and an isoniazid-resistant clinical isolate of MTB. The compounds 6b, 6c, 6d, 6k, 7b, 7c, 7d and 7k exhibited promising antibacterial activity MIC in the range of 15-73 μM against all bacterial strains used and compounds 6d and 7b showed antimycobacterial activity (IC50 <340 μM in LRP assay) and (MIC <9 μM in broth microdilution method).
Fulltext Transcriptome analysis of Escherichia coli K1 after therapy with hesperidin conjugated with silver nanoparticles

Masri A, Khan NA, Zoqratt MZHM, Ayub Q, Anwar A, Rao K, et al.

BMC Microbiol, 2021 Feb 17;21(1):51.
PMID: 33596837 DOI: 10.1186/s12866-021-02097-2

BACKGROUNDS: Escherichia coli K1 causes neonatal meningitis. Transcriptome studies are indispensable to comprehend the pathology and biology of these bacteria. Recently, we showed that nanoparticles loaded with Hesperidin are potential novel antibacterial agents against E. coli K1. Here, bacteria were treated with and without Hesperidin conjugated with silver nanoparticles, and silver alone, and 50% minimum inhibitory concentration was determined. Differential gene expression analysis using RNA-seq, was performed using Degust software and a set of genes involved in cell stress response and metabolism were selected for the study.
RESULTS: 50% minimum inhibitory concentration with silver-conjugated Hesperidin was achieved with 0.5 μg/ml of Hesperidin conjugated with silver nanoparticles at 1 h. Differential genetic analysis revealed the expression of 122 genes (≥ 2-log FC, P
Self-assembled micelles loaded with itraconazole as anti-Acanthamoeba nano-formulation

Rao K, Abdullah M, Ahmed U, Wehelie HI, Shah MR, Siddiqui R, et al.

Arch Microbiol, 2024 Mar 04;206(4):134.
PMID: 38433145 DOI: 10.1007/s00203-024-03854-3

Acanthamoeba castellanii are opportunistic pathogens known to cause infection of the central nervous system termed: granulomatous amoebic encephalitis, that mostly effects immunocompromised individuals, and a sight threatening keratitis, known as Acanthamoeba keratitis, which mostly affects contact lens wearers. The current treatment available is problematic, and is toxic. Herein, an amphiphilic star polymer with AB2 miktoarms [A = hydrophobic poly(ℇ-Caprolacton) and B = hydrophilic poly (ethylene glycol)] was synthesized by ring opening polymerization and CuI catalyzed azide-alkyne cycloaddition. Characterization by 1H and 13C NMR spectroscopy, size-exclusion chromatography and fluorescence spectroscopy was accomplished. The hydrophobic drug itraconazole (ITZ) was incorporated in self-assembled micellar structure of AB2 miktoarms through co-solvent evaporation. The properties of ITZ loaded (ITZ-PCL-PEG2) and blank micelles (PCL-PEG2) were investigated through zeta sizer, scanning electron microscopy and Fourier-transform infrared spectroscopy. Itraconazole alone (ITZ), polymer (DPB-PCL), empty polymeric micelles (PCL-PEG2) alone, and itraconazole loaded in polymeric micelles (ITZ-PCL-PEG2) were tested for anti-amoebic potential against Acanthamoeba, and the cytotoxicity on human cells were determined. The polymer was able to self-assemble in aqueous conditions and exhibited low value for critical micelle concentration (CMC) 0.05-0.06 µg/mL. The maximum entrapment efficiency of ITZ was 68%. Of note, ITZ, DPB, PCL-PEG2 and ITZ-PCL-PEG2 inhibited amoebae trophozoites by 37.34%, 36.30%, 35.77%, and 68.24%, respectively, as compared to controls. Moreover, ITZ-PCL-PEG2 revealed limited cytotoxicity against human keratinocyte cells. These results are indicative that ITZ-PCL-PEG2 micelle show significantly better anti-amoebic effects as compared to ITZ alone and thus should be investigated further in vivo to determine its clinical potential.
Bell Palsy: Facts and Current Research Perspectives

Rajangam J, Lakshmanan AP, Rao KU, Jayashree D, Radhakrishnan R, Roshitha B, et al.

CNS Neurol Disord Drug Targets, 2024;23(2):203-214.
PMID: 36959147 DOI: 10.2174/1871527322666230321120618

Bell palsy is a non-progressive neurological condition characterized by the acute onset of ipsilateral seventh cranial nerve paralysis. People who suffer from this type of facial paralysis develop a droop on one side of their face, or sometimes both. This condition is distinguished by a sudden onset of facial paralysis accompanied by clinical features such as mild fever, postauricular pain, dysgeusia, hyperacusis, facial changes, and drooling or dry eyes. Epidemiological evidence suggests that 15 to 23 people per 100,000 are affected each year, with a recurrence rate of 12%. It could be caused by ischaemic compression of the seventh cranial nerve, which could be caused by viral inflammation. Pregnant women, people with diabetes, and people with respiratory infections are more likely to have facial paralysis than the general population. Immune, viral, and ischemic pathways are all thought to play a role in the development of Bell paralysis, but the exact cause is unknown. However, there is evidence that Bell's hereditary proclivity to cause paralysis is a public health issue that has a greater impact on patients and their families. Delay or untreated Bell paralysis may contribute to an increased risk of facial impairment, as well as a negative impact on the patient's quality of life. For management, antiviral agents such as acyclovir and valacyclovir, and steroid treatment are recommended. Thus, early diagnosis accompanied by treatment of the uncertain etiology of the disorder is crucial. This paper reviews mechanistic approaches, and emerging medical perspectives on recent developments that encounter Bell palsy disorder.
Fulltext Treosulfan and Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Children with Primary Immunodeficiency: UK Experience

Slatter MA, Rao K, Abd Hamid IJ, Nademi Z, Chiesa R, Elfeky R, et al.

Biol. Blood Marrow Transplant., 2018 03;24(3):529-536.
PMID: 29155317 DOI: 10.1016/j.bbmt.2017.11.009

We previously published results for 70 children who received conditioning with treosulfan and cyclophosphamide (n = 30) or fludarabine (n = 40) before undergoing hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency (PID). Toxicity was lower and T cell chimerism was better in the patients receiving fludarabine, but cohort numbers were relatively small and follow-up was short. Here we report outcomes of 160 children who received homogeneous conditioning with treosulfan, fludarabine, and, in most cases, alemtuzumab (n = 124). The median age at transplantation was 1.36 years (range, .09 to 18.25 years). Donors included 73 matched unrelated, 54 1 to 3 antigen-mismatched unrelated, 12 matched sibling, 17 other matched family, and 4 haploidentical donors. Stem cell source was peripheral blood stem cells (PBSCs) in 70, bone marrow in 49, and cord blood in 41. Median duration of follow-up was 4.3 years (range, .8 to 9.4 years). Overall survival was 83%. No patients had veno-occlusive disease. Seventy-four patients (46%) had acute GVHD, but only 14 (9%) greater than grade II. Four patients underwent successful retransplantation for graft loss or poor immune reconstitution. Another patient experienced graft rejection and died. There was no association between T cell chimerism >95% and stem cell source, but a significant association was seen between myeloid chimerism >95% and use of PBSCs without an increased risk of significant GVHD compared with other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth were alive at up to 8.7 years of follow-up. Long-term studies are needed to determine late gonadotoxic effects, and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine, and alemtuzumab is associated with excellent results in HSCT for PID.
Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors

Takhi M, Sreenivas K, Reddy CK, Munikumar M, Praveena K, Sudheer P, et al.

Eur J Med Chem, 2014 Sep 12;84:382-94.
PMID: 25036796 DOI: 10.1016/j.ejmech.2014.07.036

A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-positive pathogens particularly staphylococcal organisms. Most of the compounds from the series possessed excellent biochemical inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clinically relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, AEA16, in Escherichia coli FabI enzyme was determined unambiguously using X-ray crystallography. The lead compounds displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.

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