Faculty Directory

Syed K. AhmedPhD

Syed K. AhmedPhD

Adjunct Research Assistant Professor of Clinical Pharmacy; Associate Director, Medicinal Chemistry Core

Syed Kaleem Ahmed trained as an organic and medicinal chemist; he has 16 years of post-Ph.D. experience. His research interests focus on development of antiviral, anticancer, PROTACS, central nervous system agents as well as Fluorine-18 and Carbon-11 labeled radiotracers for imaging of brain disorders, cancer diseases using positron emission tomography (PET). After obtaining PhD degree under the mentorship of Dr. Kamal, he joined Prof. Chuck Thompson’s group as a Postdoctoral Fellow in 2008. During this time, he had the opportunity to gain an unique experience in organophosphate and small molecule chemistry focusing on CNS related therapeutic targets. This work resulted in US-patents as well as publications in peer-reviewed reputed journals. He continued his second postdoctoral work with Prof. Wayne J. Brouillette at the University of Alabama, where he got an extensive experience in total synthesis and at his third postdoctoral work with Prof. John M Gerdes & Prof. Chuck Thompson at University of Montana he designed and developed a Fluorine-18 labeled PET-imaging ligand for treating neurodegenerative disorders which is currently completed phase II trials (WO 2013/134241 A1). He continued in the department of Biomedical and Pharmaceutical sciences, at the University of Montana as a senior research scientist and made several discoveries, which were later published or protected through patents. At Southern Research, as a lead medicinal chemist he contributed to several projects, which resulted in successful development of several small molecule antiviral compounds, some of which advanced to clinical studies. This has resulted in several patents, and publications. He is presently working on multiple projects and grant collaborations as well as mentoring graduate and undergraduate students at USC where he serves as an Associate Director of Medicinal Chemistry core, and Faculty member at the Keck School of Medicine.

Areas of Expertise

  • Organic Synthesis
  • Medicinal Chemistry
  • Drug Design and Discovery
  • Bioorthogonal Chemistry
  • Education

    Indian Institute of Chemical Technology

    PhD

    Osmania University

    MS

  • Links
  • Selected Articles

    Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors

    J. Med. Chem. 2021, 64(8), 4762–4786
    Ahmed, S.K.; Haese, N.N.; Cowan, J. T.; Pathak, V.; Chafiq, O. M; Smith, V. J.; Rodzinak, K. J.; Ahmad, F.; Zhang, S.; Bonin, K. M.; Streblow, A. D.; Streblow, C. E.; Kreklywich, C. N.; Morrison, C.; Sarkar, S.; Moorman, N.; Sander, W.; Allen, R.; DeFilippis, V.; Tekwani, B. L.; Wu, M.; Hirsch, A. J.; Smith, J. L.; Tower, N. A.; Rasmussen, L.; Bostwick, R.; Maddry, J. A.; Ananthan, S.; Gerdes, J. M.; Augelli-Szafran, C. E.; Suto, M. J.; Morrison, T. E.; Heise, M. T.; Streblow, D. N.; Ashish K. Pathak, A. K

    A benzo[6]annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC90 = 1.45 μM and viral titer reduction (VTR) of 2.5 log at 10 μM with no observed cytotoxicity (CC50 = 169 μM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity (EC90 = 270 nM and VTR of 4.5 log at 10 μM) and improved liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage pathway

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    Synthesis and anti-acetylcholinesterase properties of novel β- and γ-substituted alkoxy organophosphonates

    Bioorg Med Chem Lett . 2013;23(7):2048-51
    Ahmed, S. K.; Belabassi, Y.; Sankaranarayanan, L.; Chao, C. K.; Gerdes, J. M.; Thompson, C. M.

    Activated organophosphate (OP) insecticides and chemical agents inhibit acetylcholinesterase (AChE) to form OP-AChE adducts. Whereas the structure of the OP correlates with the rate of inhibition, the structure of the OP-AChE adduct influences the rate at which post-inhibitory reactivation or aging phenomena occurs. In this report, we prepared a panel of β-substituted ethoxy and γ-substituted propoxy phosphonoesters of the type p-NO(2)PhO-P(X)(R)[(O(CH(2))(n)Z] (R=Me, Et; X=O, S; n=2, 3; Z=halogen, OTs) and examined the inhibition of three AChEs by select structures in the panel. The β-fluoroethoxy methylphosphonate analog (R=Me, Z=F, n=2) was the most potent anti-AChE compound comparable (ki ∼6 × 10(6)M(-1)min(-1)) to paraoxon against EEAChE. Analogs with Z=Br, I, or OTs were weak inhibitors of the AChEs, and methyl phosphonates (R=Me) were more potent than the corresponding ethyl phosphonates (R=Et). As expected, analogs with a thionate linkage (PS) were poor inhibitors of the AChEs.

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    Use of the hydantoin isostere to produce inhibitors showing selectivity toward the vesicular glutamate transporter versus the obligate exchange transporter system x(c)(-)

    Bioorg Med Chem Lett . 2011 ;21(14):4358-62
    Ahmed, S. K.; Etoga, J. L. G.; Patel, S. A.; Bridges, R. J.; Thompson, C. M

    Evidence was acquired prior to suggest that the vesicular glutamate transporter (VGLUT) but not other glutamate transporters were inhibited by structures containing a weakly basic α-amino group. To test this hypothesis, a series of analogs using a hydantoin (pK(a)∼9.1) isostere were synthesized and analyzed as inhibitors of VGLUT and the obligate cystine-glutamate transporter (system x(c)(-)). Of the hydantoin analogs tested, a thiophene-5-carboxaldehyde analog 2l and a bis-hydantoin 4b were relatively strong inhibitors of VGLUT reducing uptake to less than 6% of control at 5mM but few inhibited system x(c)(-) greater than 50% of control. The benzene-2,4-disulfonic acid analog 2b and p-diaminobenzene analog 2e were also good hydantoin-based inhibitors of VGLUT reducing uptake by 11% and 23% of control, respectively, but neither analog was effective as a system x(c)(-) inhibitor. In sum, a hydantoin isostere adds the requisite chemical properties needed to produce selective inhibitors of VGLUT.

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    A novel fluorine-18 β-fluoroethoxy organophosphate positron emission tomography imaging tracer targeted to central nervous system acetylcholinesterase

    ACS Chem Neurosci . 2014 ;5(7):519-24
    Shelly, J.; Ahmed, S.K.; Stephanie, M.; Braden, M.; Belabassi, Y.; VanBrocklin, H.; Thompson, C.; Gerdes, J

    Radiosynthesis of a fluorine-18 labeled organophosphate (OP) inhibitor of acetylcholinesterase (AChE) and subsequent positron emission tomography (PET) imaging using the tracer in the rat central nervous system are reported. The tracer structure, which contains a novel β-fluoroethoxy phosphoester moiety, was designed as an insecticide-chemical nerve agent hybrid to optimize handling and the desired target reactivity. Radiosynthesis of the β-fluoroethoxy tracer is described that utilizes a [(18)F]prosthetic group coupling approach. The imaging utility of the [(18)F]tracer is demonstrated in vivo within rats by the evaluation of its brain penetration and cerebral distribution qualities in the absence and presence of a challenge agent. The tracer effectively penetrates brain and localizes to cerebral regions known to correlate with the expression of the AChE target. Brain pharmacokinetic properties of the tracer are consistent with the formation of an OP-adducted acetylcholinesterase containing the fluoroethoxy tracer group. Based on the initial favorable in vivo qualities found in rat, additional [(18)F]tracer studies are ongoing to exploit the technology to dynamically probe organophosphate mechanisms of action in mammalian live tissues.

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    Conformationally-restricted amino acid analogues bearing a distal sulfonic acid show selective inhibition of system x(c)(-) over the vesicular glutamate transporter

    Bioorg Med Chem Lett . 2010 ;20(8):2680-3
    Etoga, J. L. E.; Ahmed, S. K.; Patel, S.; Bridges, R. J.; Thompson. C. M.

    A panel of amino acid analogs and conformationally-restricted amino acids bearing a sulfonic acid were synthesized and tested for their ability to preferentially inhibit the obligate cysteine-glutamate transporter system x(c)(-) versus the vesicular glutamate transporter (VGLUT). Several promising candidate molecules were identified: R/S-4-[4'-carboxyphenyl]-phenylglycine, a biphenyl substituted analog of 4-carboxyphenylglycine and 2-thiopheneglycine-5-sulfonic acid both of which reduced glutamate uptake at system x(c)(-) by 70-75% while having modest to no effect on glutamate uptake at VGLUT.

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  • Patents

    Substituted phenyl ethynyl pyridine carboxamides as potent inhibitors of SARS virus

    US20230192733A1 | 2023

    Coronaviruses are single-stranded, RNA viruses with a large genome in which mutations are very common. There are seven known human types of coronavirus: 229E, OC43, NL63, HKU1, which are often associated with mild upper respiratory tract infections, as well as the virus causing severe acute respiratory syndrome (SARS-CoV), Middle East respiratory syndrome (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), each of which are zoonotic but have also caused human disease. Interspecies transmission and the resulting emergent coronaviruses have been important factors in emerging respiratory disease as coronaviruses are known to infect feline, swine, canine, and bat species. Indeed, MERS-CoV, SARS-CoV, and SARS-CoV-2 emerged from animal reservoirs and are now increasingly important respiratory virus threats. To date, over 239 million cases of SARS-CoV-2 have been confirmed in humans, resulting in over 4,500,000 deaths. Thus, there remains a need for potent therapies that can ameliorate coronavirus infection. These needs and others are met by the present invention.

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    Cholinesterase Inhibitors

    US20130343994A1 | 2013

    The invention provides compounds that inhibit cholinesterases, such as acetylcholinesterase and butyrylcholinesterase. Such compounds are useful to prevent or treat exposure of a patient (e.g., a human) to an organophosphoric nerve agent (e.g., sarin and VX) or to treat a patient suffering from a neurodegenerative disorder such as Alzheimer's Disease or Lewy Body Dementia. The compounds are further useful as diagnostic tools for use in medical or research radiography (e.g., positron emission tomography) when synthesized with a radionuclide (e.g., [18F]. Synthetic schemes to produce such compounds are also provided.

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    Aspartylamide inhibitors of excitatory amino acid transporters

    WO2013/134241 | 2013

    The compounds of the invention are inhibitors of excitatory amino acid transporters (EAAT) that penetrate the blood-brain barrier to access the central nervous system. The compounds of the invention follow the structural formula: or a salt, ester or prodrug thereof, wherein X is a halogen, such as fluorine, or a radionuclide, such as fluorine-18. The compounds and methods described herein can be used for the treatment of, e.g., neurodegenerative disorders (e.g., amyotrophic lateral sclerosis), ischemia, spinal cord injury, and traumatic brain injury in a patient (e.g., a human). The invention further provides compounds and methods for the synthesis and use of radiographic tracers to diagnose and follow the progression of such disorders

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    4-SUBSTITUTED-2-THIAZOLE AMIDES AS ANTIVIRAL AGENTS

    US20200399264A1 | 2020

    The present disclosure is concerned with benzoannulene compounds that are capable of inhibiting a viral infection and methods of treating viral infections such as, for example, chikungunya, Venezuelan equine encephalitis, Eastern equine encephalitis, Western equine encephalitis, dengue, West Nile, influenza, and zika, using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

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    Benzo annulenes as antiviral agents

    US10450263B2 | 2019

    The present disclosure is concerned with benzo annulene compounds that are capable of inhibiting a viral infection and methods of treating viral infections such as, for example, chikungunya, Venezuelan equine encephalitis, dengue, influenza, and zika, using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

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    Benzoannulene derivatives as antiviral agents

    US011066357B2 | 2021

    The present disclosure is concerned with benzoannulene compounds that are capable of inhibiting a viral infection and methods of treating viral infections such as, for example, chikungunya, Venezuelan equine encephalitis, dengue, influenza, and zika, using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

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    Substituted Phenyl Ethynyl Pyrimidines as Potent Inhibitors of Alphaviruses

    19044.0462U1 | 2023

    In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compositions and methods for use in the prevention and treatment of viral infections such as, for example, chikungunya (CHIKV), Western Equine Encephalitis virus (WEEV), Eastern Equine Encephalitis virus (EEEV) and Venezuelan equine encephalitis (VEEV)

    Methods for Producing N-(Chroman-3-yl) Benzamide Analogs as Potent Antimicrobial and Immunomodulating Agents

    US Provisional Application No. 63/639, 449 | 2024

    The present disclosure provides compounds, compositions, and methods for the treatment and prevention of infectious diseases such as those associated with Staphylococcus aureus

    2-OXO-2H-CHROMEN-3-YL) SCAFFOLD BASED CARBOXAMIDE ANALOGS AS POTENT INHIBITORS OF TAU PROTEIN FIBRILS

    US Provisional Application No. 63/681,541 | 2024

    The present invention relates generally to the field of chemistry, particularly organic chemistry and medicinal chemistry. More particularly, it concerns compounds, compositions, and methods for the treatment and prevention of neurodegenerative diseases and disorders, such as Alzheimer’s disease.