Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
Presented by Shikha Popali and Harshpal singh Wahi students from Gurunanak college of pharmacy, Nagpur in Department of pharmaceutical Chemistry. The explained topic is seful for every chemistry student and for others too
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
Presented by Shikha Popali and Harshpal singh Wahi students from Gurunanak college of pharmacy, Nagpur in Department of pharmaceutical Chemistry. The explained topic is seful for every chemistry student and for others too
ENZYME INHIBITION THE MOST IMPORTANT TOPIC FOR BIOLOGY AS WELL AS CHEMISTRY PEOPLES. WE HAVE HERE COVERED FOR THE PHARMA STUDENTS THIS WILL MAKE THEM EASY AS WE ARE COLLECTED ALL THE DATA A SINGLE PLACE WICH COVERS ALL THE COTENTS.
Penicillin, one of the first and still one of the most widely used antibiotic agents, is derived from the penicillium mold. In 1928 Scottish bacteriologist alexander fleming in a contaminated green mold penicillium notatum. He isolated the mold, grew it in a fluid medium, and found that it produced a substance capable of killing many of the common bacteria that infect humans. Australian pathologist howard florey and British biochemist ernst Boris chain isolated and purified penicillin in the late 1930s, and by 1941 an injectable form of the drug was available for therapeutic use.
Penicillin's are beta lactam antibiotics and characterized by three fundamental structural requirements
The fused beta-lactam and thiazolidine ring structure.
free carboxylic acid group.
And one or more substituted acylamino side chain.
Penam nucleus: 7-oxo-l-thia-4-azabicyclo [3.2.0] heptane
Absolute configuration: 3-S, 5-R, 6-R.
Instrumental methods of characterization:
FTIR
MASS
C13-NMR
1H-NMR
FTIR: -
Penicillin G molecule and its IR spectra in D2 O and in DMSO. Spectra are characterized by the presence of three intense bands.
β- lactam CO stretching observe at 1761 cm-1 in D2O and 1762 cm-1 in DMSO solution.
Amide group is observe at 1640 cm-1 in D2O and 1674 cm-1 in DMSO solution.
Asymmetric stretching of carboxylate group is observe at 1601 cm-1 in D20 and 1615 cm-1 in DMSO solution.
A large red shift of amide , out of the frequency window, is observed upon proton exchange in DMSO.
Collision-Induced Dissociation (CID) technique
MASS:-
A high-resolution, hybrid tandem mass spectrometer was used to obtain CID spectra. The CID spectra were acquired by:
Mass selecting the precursor ions using the first mass spectrometer.
Injecting the ions into the first quadrupole (collision cell) where they undergo CID.
Mass-analyzing the fragment ions produced using the second quadrupole.
Argon was used as the collision gas, and the pressure in the collision cell was adjusted to attenuate the precursor ion intensity to 20-50% of the original intensity. The collision energy of the ions ranged from 160 to 180 eV. The mass spectra shown abundant fragmentations at m/z 160 and m/z 176 that were reported to arise from cleavage of the β-lactam ring.
protonated benzyl penicillin exhibits abundant fragment ions at m/z 160, m/z 176, m/z 217, m/z 128, and m/z 289. The most abundant CID fragment at m/z 160 and the molecular ion peak was observed at m/z 334.
C13-NMR: -
The four sp3 ring carbons give rise to resonances in the decreasing chemical shift order C-3, C-5, C-2 and C-6.
Chemical shift for C-2 is 64.9 ppm and the substituents attached with it are α-methyl 27.0 ppm and β-methyl 31.4 ppm. Chemical shift for C-3 is 73.6 ppm and 174.5 ppm for carboxylate functions (reflecting the smaller de-shielding influence of COOH over that of COO-). The chemic shift for C-5 is 67.2 ppm. The chemic shift for C-6 is 58.4 ppm.
The lactam group shows its chemical shift at 175.0 ppm
Amino group
Contents includes at least three strategies of synthesis for each of three, four, five and six membered heterocylic ring with one or two heteroatoms. One mechanism described out of the three strategies. Few name reactions are described and the other are simple synthetic methods. This presentation was prepared for the partial fulfillment of Master of Pharmacy. The content was taken from the various books, mentioned in slide with the title of references.
There are many ways that drug-resistant infections can be prevented: immunization, safe food preparation, handwashing, and using antibiotics as directed and only when necessary. In addition, preventing infections also prevents the spread of resistant bacteria.The main cause of antibiotic resistance is antibiotic use. When we use antibiotics, some bacteria die but resistant bacteria can survive and even multiply. The overuse of antibiotics makes resistant bacteria more common. The more we use antibiotics, the more chances bacteria have to become resistant to them.
ENZYME INHIBITION THE MOST IMPORTANT TOPIC FOR BIOLOGY AS WELL AS CHEMISTRY PEOPLES. WE HAVE HERE COVERED FOR THE PHARMA STUDENTS THIS WILL MAKE THEM EASY AS WE ARE COLLECTED ALL THE DATA A SINGLE PLACE WICH COVERS ALL THE COTENTS.
Penicillin, one of the first and still one of the most widely used antibiotic agents, is derived from the penicillium mold. In 1928 Scottish bacteriologist alexander fleming in a contaminated green mold penicillium notatum. He isolated the mold, grew it in a fluid medium, and found that it produced a substance capable of killing many of the common bacteria that infect humans. Australian pathologist howard florey and British biochemist ernst Boris chain isolated and purified penicillin in the late 1930s, and by 1941 an injectable form of the drug was available for therapeutic use.
Penicillin's are beta lactam antibiotics and characterized by three fundamental structural requirements
The fused beta-lactam and thiazolidine ring structure.
free carboxylic acid group.
And one or more substituted acylamino side chain.
Penam nucleus: 7-oxo-l-thia-4-azabicyclo [3.2.0] heptane
Absolute configuration: 3-S, 5-R, 6-R.
Instrumental methods of characterization:
FTIR
MASS
C13-NMR
1H-NMR
FTIR: -
Penicillin G molecule and its IR spectra in D2 O and in DMSO. Spectra are characterized by the presence of three intense bands.
β- lactam CO stretching observe at 1761 cm-1 in D2O and 1762 cm-1 in DMSO solution.
Amide group is observe at 1640 cm-1 in D2O and 1674 cm-1 in DMSO solution.
Asymmetric stretching of carboxylate group is observe at 1601 cm-1 in D20 and 1615 cm-1 in DMSO solution.
A large red shift of amide , out of the frequency window, is observed upon proton exchange in DMSO.
Collision-Induced Dissociation (CID) technique
MASS:-
A high-resolution, hybrid tandem mass spectrometer was used to obtain CID spectra. The CID spectra were acquired by:
Mass selecting the precursor ions using the first mass spectrometer.
Injecting the ions into the first quadrupole (collision cell) where they undergo CID.
Mass-analyzing the fragment ions produced using the second quadrupole.
Argon was used as the collision gas, and the pressure in the collision cell was adjusted to attenuate the precursor ion intensity to 20-50% of the original intensity. The collision energy of the ions ranged from 160 to 180 eV. The mass spectra shown abundant fragmentations at m/z 160 and m/z 176 that were reported to arise from cleavage of the β-lactam ring.
protonated benzyl penicillin exhibits abundant fragment ions at m/z 160, m/z 176, m/z 217, m/z 128, and m/z 289. The most abundant CID fragment at m/z 160 and the molecular ion peak was observed at m/z 334.
C13-NMR: -
The four sp3 ring carbons give rise to resonances in the decreasing chemical shift order C-3, C-5, C-2 and C-6.
Chemical shift for C-2 is 64.9 ppm and the substituents attached with it are α-methyl 27.0 ppm and β-methyl 31.4 ppm. Chemical shift for C-3 is 73.6 ppm and 174.5 ppm for carboxylate functions (reflecting the smaller de-shielding influence of COOH over that of COO-). The chemic shift for C-5 is 67.2 ppm. The chemic shift for C-6 is 58.4 ppm.
The lactam group shows its chemical shift at 175.0 ppm
Amino group
Contents includes at least three strategies of synthesis for each of three, four, five and six membered heterocylic ring with one or two heteroatoms. One mechanism described out of the three strategies. Few name reactions are described and the other are simple synthetic methods. This presentation was prepared for the partial fulfillment of Master of Pharmacy. The content was taken from the various books, mentioned in slide with the title of references.
There are many ways that drug-resistant infections can be prevented: immunization, safe food preparation, handwashing, and using antibiotics as directed and only when necessary. In addition, preventing infections also prevents the spread of resistant bacteria.The main cause of antibiotic resistance is antibiotic use. When we use antibiotics, some bacteria die but resistant bacteria can survive and even multiply. The overuse of antibiotics makes resistant bacteria more common. The more we use antibiotics, the more chances bacteria have to become resistant to them.
The relationship between bioisosteres, substituents or group with physical or chemical properties that impart similar biological properties to a chemical structure
e-content of Stereochemistry for Pharmacy and Chemistry students.
contents includes Isomerism, Chirality, Stereoisomers, Enantiomer, Diastereomer, Cis And Trans Configuration ,L And D Configuration ,R And S Configuration and Importance of the chirality in drugs ,Intravenous anaesthetics , etc.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
1. ANALOG DESIGN
Presented by,
Komal Bajaj
Mohit Umare
M. Pharm First Year (2019-20)
Department of Pharmceutical Sciences RTM Nagpur University,
Nagpur.440033
1
2. CONTENTS
• INTRODUCTION
• BIOISOSTERIC REPLACEMENT
• RIGID ANALOG
• ALTERATION OF CHAIN BRANCHING
• CHANGE IN RING SIZE
• RING POSITION ISOMERS
• STEREO ISOMERS
• GEOMERTRIC ISOMERS
• FRAGMENTS OF THE LEAD MOLECULE
• VARIATION IN INTERATOMIC DISTANCES
• REFERENCES
2
3. INTRODUCTION
Definition
• Analog design is usually defined as the
modification of a drug molecule or of any
bioactive compound in order to prepare a new
molecule showing chemical and biological
similarity with the original model compound
3
4. GOALS OF ANALOG DESIGN
• To modify the chemical structure of the lead com-
pound to retain or to reinforce the desirable
pharmacologic effect while minimizing un-
wanted pharmacological , physical and chemical
properties, which may result in a superior
therapeutic agent.
• To use target analogs as pharmacological probes
to gain better insight into the pharmacology of
the lead molecule and perhaps to reveal new
knowledge of basic biology.
4
5. CATEGORIES OF ANALOGS
1] Analogs possessing chemical and
pharmacological similarities:
• The first class of analogs, simultaneously having
chemical and pharmacological similarities, can
be considered as “directanalogs” .
• These analogs correspond to the category of
drugs often referred to as“metoodrugs”.
• Usually,they are an advantage to the consumer
.In the case of drugs, this means that they
provide an advance in therapeutic benefit.
5
6. CATEGORIES OF ANALOGS
2] Analogs possessing only chemical
similarities:
• The second class, made of “structural analogs,”
contains compounds originally prepared as close
and patentable analogs of a novel lead, but for
which the biological assays revealed totally
unexpected pharmacological properties.
• Observation of the new activity can be purely by
chance but can also result from a planned
systematic investigation.
6
7. CATEGORIES OF ANALOGS
3] Compounds chemically different, but
displaying similar pharmacological
properties:
• Third class of analogs, chemical similarity is not
observed; however, they share common
biological properties.
• We propose the term “functional analogs” for
such compounds.
7
8. Strategies for molecular modification
of the lead compound
1. Bioisosteric replacement.
2. Design of rigid analogs.
3. Homologation of alkyl chain(s) or alteration of chain
branching, design of aromatic ring-position isomers,
alteration of ring size, and substitution of an aromatic
ring for a saturated one, or the converse.
4. Alteration of stereochemistry, or design of geometric
isomers or stereoisomers.
5. Design of fragments of the lead molecule that contain
the pharmacophoric group (bond disconnection).
6. Alteration of interatomic distances within the
pharmacophoric group or in other parts of the molecule.
8
9. 1] BIOISOSTERIC REPLACEMENT
• Bioisosteres are groups or molecules which
have chemical and physical properties
producing broadly similar biological properties
• This definition might be modified to include
the concept that bioisosteres may produce
opposite biological effects, and these effects
are frequently a reflection of some action on
the same biological process or at the same
receptor site.
9
11. 1] BIOISOSTERIC REPLACEMENT
Classification:
Bioisosteres have been classified into classical
and non-classical bioisosteres.
Bioisosteres
Classical
Same stearic and
electronic properties
Non-
classical
Different stearic and
electronic properties
11
12. 1] BIOISOSTERIC REPLACEMENT
Classical Bioisoster :
• Monovalent atoms or groups.
• Divalent atoms or groups.
• Trivalent atoms or groups.
• Tetra substituted atoms.
• Ring equivalents.
12
13. 1] BIOISOSTERIC REPLACEMENT
13
Monovalent atoms or groups.
D and H
F and H
NH2 and OH
RSH and ROH
F, OH ,NH2, and CH3
CL , Br , SH ,and OH
Fig. Bioisoisteric H/F Replacement
19. 1] BIOISOSTERIC REPLACEMENT
Cyclic vs Non Cyclic
Fig. Replacement of a cyclic system with an acyclic derivative from
estradiol to trans-diethylstilbestrol.
19
27. 2] RIGID ANALOG
Imposition of some degree of molecular rigidity
on a flexible organic molecule may result in
potent, biologically active agents that show a
higher degree of specificity of pharmacologic
effect.
27
28. 2] RIGID ANALOG
Advantages:
• The key functional groups are held in one steric
disposition.
• By the rigid analog strategy, it is possible to
approximate "frozen" conformations of a
flexible lead molecule that, if an enhanced
pharmacological effect results, may assist in
defining and understanding structure activity
parameters, including the three dimensional
geometry of the pharmacophore.
28
29. 2] RIGID ANALOG
29
• Restriction of conformational freedom of the acyl moiety in 4-DAMP
(Diphenylacetoxypiperidinium ) an antimuscarinic compound displaying
higher affinity at M3, acetylcholine receptors than at atrial M2, receptors was
imposed by the structure of the spiro-compound.
• Spiro-DAMP was slightly more potent at M2, muscarinic receptors than at
M3, receptors.
30. 3] ALTERATION OF CHAIN BRANCHING
• Change in size or branching of an alkyl chain on a
bioactive molecule may have profound (and sometimes
unpredictable) effects on physical and pharmacological
properties.
• Alteration of the size and or shape of an alkyl substituent
can affect the conformational preference of a flexible
molecule and may alter the relationships of the
components of the pharmacophore, which may be reflected
in the ability of the molecule to achieve complementarity
with its receptor or with the catalytic surface of a
metabolizing enzyme.
• The alkyl group itself may represent a binding site with
the receptor (through hydrophobic interactions), and
alteration of the chain may alter its binding capacity.
30
31. 3] ALTERATION OF CHAIN BRANCHING
31
• Alteration in N-alkyl chain in norapomorphine from methyl to n-
propyl produced incremental increase in emetic response.
• n-butyl homolog demostrated a tremendous loss in potency and
activity .
32. 4] CHANGE IN RING SIZE
• In a series of spiro-tetraoxacycloalkanes,with varying
heterocyclic ring sizes, it was found that the compound where
n = 1 demonstrated marked antimalarial activity against P.
bergei and P. falciparum, and showed low toxicity.
• The analog in which n = 4 showed strong activity against P.
falciparum but it was unimpressive in the P. bergei assay.
32
33. 5] RING POSITION ISOMERS
• Positional isomers are constitutional Isomers
that have the same carbon skeleton and the
same functional group but differ from each
other in the location of the functional
groups on or in the carbon chain.
• Position isomers of substituents (even alkyl
groups) on an aromatic ring may possess
different pharmacological properties.
33
34. 5] RING POSITION ISOMERS
In a series of arylsulfonamidophenethanolamines ,
derivatives bearing the sulfonamido group meta to the
ethanolamine side chain displayed properties of a β-
adrenoceptor partial agonist, whereas 19
compounds bearing the sulfonamido group in the para
position were β-antagonists.
34
35. 6] STEREO ISOMERS
• Stereoisomers are molecules that have the
same molecular formula and differ only in
how their atoms are arranged in three-
dimensional space.
• All stereoisomers of an organic molecule will
exhibit pharmacological effects, frequently
widely different and unpredictable.
35
36. 6] STEREO ISOMERS
36
(+-)3-(3-Hydroxypheny1)-
N-n-propylpiperidine
R enantiomer: At high doses
selectively stimulated
presynaptic dopaminergic
receptor sites,
whereas at lower doses it
selectively stimulated
postsynaptic receptor sites.
S enantiomer: stimulated
presynaptic dopamine receptors
and at the same dose level, it
blocked postsynaptic dopamine
receptors.
37. 7] GEOMERTRIC ISOMERS
• Geometric isomers are molecules in which
each of two or more chemical compounds having
the same molecular formula but a different
geometric arrangement;an unsaturated
compound or ring compound in which rotation
around a carbon bond is restricted, as in cis- and
trans- configurations.
• cis- and trans-4-Aminocrotonic acid and
were prepared as congeners of Gama
aminobutyric acid (GABA).
37
38. • The folded 2-isomer was inactive in assays
for GABA agonism, whereas the ex- tended
E-isomer was active.
• These data demonstrate biological differences
of geometric isomers.
38
7] GEOMERTRIC ISOMERS
39. • Lead molecules present in polycyclic natural
products may be much more structurally complex
than in necessary for optimal pharmacological
effect.
• Pharmacophoric moiety may be buried within the
complex structure of the lead compound.
• This pharmacophore can be dissect out chemically.
• The result may be biologically active, simpler
molecules that may themselves be used as leads in
further analog design.
39
8] FRAGMENTS OF THE LEAD
MOLECULE
40. • STRATEGY
A bond disconnection strategy may be employed
in which bonds in the polycyclic structure are
broken or removed to destroy one or more of the
rings.
40
8] FRAGMENTS OF THE LEAD
MOLECULE
Example :Morphine as a lead molecule for
which fragment analog design has been
used.
Morphine
42. Alteration of distances between portions of
the pharmacophore of a molecule (or even
between other portions of the molecule) may
produce profound qualitative and/or quantitative
changes in pharmacological actions.
42
9] VARIATION IN INTERATOMIC
DISTANCES
43. • In bis-trimethylammonium
polymethylene
Compounds showing autonomic ganglia blocking
acvtivity .
43
9] VARIATION IN INTERATOMIC
DISTANCES
n=5 or 6 maximum activity
n= 4 or 7 effect drops drastically
n= 16 0r 18 4x more potent
44. REFERENCES
44
• Burger's Medicinal Chemistry and Drug
Discovery sixth edition volume 1 edited by
Donald J. Abraham.
• Bioisosteres in Medicinal Chemistry, First
Edition. Edited by Nathan Brown 2012 Wiley-
VCH Verlag GmbH & Co. KGaA. Published 2012
by Wiley-VCH Verlag GmbH & Co. KGaA.