ANTIBIOTICSDEFINITION: These are chemical compounds or substances obtained from various kinds of microorganisms which destroy/inhibits the growth of other kinds of microorganisms at low concentration.
Classification : Based onDuration of action : short acting(half-life 6-8hrs) tetracycline chlortetracycline oxytetracyclineintermediate acting(half-life12hrs) demeclocycline methacyclinelong acting(half-life is 16hrs)
According to source : Naturally occurring Tetracycline Chlorotetracycline Demeclocycline Semi-synthetic Doxycycline Lymecycline MeclocyclineProdrugs: Rolitetracycline Lymelicycline Pipacycline Guamecycline
Tetracyclines- Ravisankar- Medicinal chemistry, Definition,classification,SAR,Mechanism of action, Side effects, uses.
1.Definition2.Introduction3.Classification4.Historical background5.Sources6.Chemistry7.SAR of tetracyclines8.Mechanism of action of tetracyclines9.Spectrum activity10.Uses of tetracyclines11.Side effects of tetracyclines
ANTIBIOTICSDEFINITION : These are chemicalcompounds or substances obtainedfrom various kinds of microorganismswhich destroy/inhibits thegrowth of other kinds ofmicroorganisms at low concentration.
Antibiotics as disturber with the bio synthesis ofprotein● These antibiotics all target the bacterial ribosome andinterfere in the process of translation of the messengerRNA into protein and thus block a fundamental processin bacterial metabolism.–Inhibitors of 30s Ribosomal subunit:Aminoglycosides and Tetracycline’s–Inhibitors of the 50s Ribosomal subunit:Macrolides and Chloramphenicol
Introduction:● Tetracyclins isolated fromStreptomyces➢ Tetracyclines are introduced 50 yearsago as potent broad spectrumantibiotics.➢They are bio synthesized from aceticacidand propionic acid unitsin microorganisms.
At present, for many reasons such astoxicity,drug resistance, the developmentof more effectives, the uses of tetracyclineshave been largely declined.* Tetracyclines possess a wide spectrum ofactivity i.e. gram+ve and gram-ve bacteria.* They are mainly designed for oral routebut parenteral and topical forms are available.
Classification :Based onDuration of action :Short acting(half-life 6-8hrs)TetracyclineChlortetracyclineOxytetracyclineIntermediate acting(half-life12hrs)DemeclocyclineMethacyclineLong acting(half-life is 16hrs)DoxycyclineMinocyclineTigecycline
According to source :Naturally occurringTetracyclineChlorotetracyclineDemeclocyclineSemi-syntheticDoxycyclineLymecyclineMeclocyclineProdrugs:RolitetracyclineLymelicyclinePipacyclineGuamecycline
Historical background● In 1945 Chlortetracycline(prototype)of tetracyclines was discovered byDr.Benjamin,M.Duggar,under theguidance of yellapragada subba Rao.● He was an employee of LederleLaboratories in U.S.A.● Dr. Duggar produced chlortetracycline(Aureomycin) form golden –colored soilbacterium called Streptomycesaureofaciens by fermentation technology.
He discovered many life saving drugs.Deficiency of Vitamin B-12 (folic Acid) causes severaldiseases. He succeeded in making folic acid in the laboratory.He discovered Aureomycine. He was the first to discover Gramicidine. Subbarao discovered Methotrexate a medicine againstcancer.Hetrazan(Diethyl carbamazine)the cure for elephantiasis.All students of biochemistry know for his pioneering workon protiens. This is now test book material. This Fisco Subbarao method got recognition amongst theworld famous scientists. He would have discovered many more medicines.But one wonders why he wasn’t awarded the Nobel Prize!
ChemistryThe basic tetracycline structure consistsof four benzene rings with variousconstituents on each ring.The crystalline bases are faintly yellow,odorless, slightly bitter compounds.They are only slightly soluble in water atpH 7 but they can form soluble sodiumsalts and hydrochloride.
STRUCTURESteriochemistry of tetracycline s is very complex.
Tetracycline pharmacophore andnumbering● Positions at the “bottom” ofthe molecule (10, 11, 1) andmost of ring A (positions 2, 3,and 4) represent the invariantpharmacophore region of themolecule, where modificationsare not tolerated without lossof antibiotic activity.
The keto-enol tatomerismBetween c2 and c3 are veryimportant for biologicalactivity.‘D’ ring should bealways aromaticChanges in this ringLeads to biologicalinactivation of the molecule. Conversion ofcorboxamide group tonitriles cause a 20 foldloss of activity.Epimerization at c4and dehydration at 5aresults loss of activity.Elimination of 6-OH groupCauses increase lipophilicityAnd more stable to acids.Ex: Doxycycline.The linearly fused tetracyclicnucleus is most importantfor the antibiotic activity.Inviolate zone is essentialLittle informationavailable.Substitution of-N(CH3)2 at 7increase the activity.Ex: Minocycline.(=CH2 at c6 increases theAntibacterial activity Ex: Methacycline).(any modification atC3 loss of activity.)Electron donating (or)electron withdrawinggroups at c7 increasedAntibacterial activity Substitution with –OH Produce water solublederivatives which canbe administered orally.Additional glycyl aminosubstitution at the 9thPosition leads to the newClass of antibioticsthe glycylcyclines.EX: Tigecycline.(Tygacil)Presence 0f-N(CH3)2 group atC4 Tetracyclines exists Ziwitter ionWhich can be posible to distribute inThe body.Removal of this group lossof activity.Replacement of –No2 group Givesmore potent but carcinogenic compounds.ABCD
Important structrual units and the three acidity constants in thetetracycline molecule.(conjugatedTrione systemIs acidic nature)(Conjugated phenolicEnone system is slightlybasic)Strong alkaline.pka1 (2.8-3.4)pka(7.2-7.8)Pka3 (9.1-9.7)
AMPHOTERIC NATURE3 structural units (3 groups are responsible for theamphoteric nature of tetracyclines.Amphoteric nature of tetracycline’s:The tetracyclines are amphoteric compounds.Amphoteric, meaning they will form salts with bothstrong acids and bases.Thus, they may exist as salts of sodium or chloride.Three structrual units of tetracyclines reprasenting3pka values.Pka1--- Conjugated trione system extending from C1 to C3of ring A is acidic nature of Pka 2.8-3.4.
Pka2--- Conjugated phenolic enone systemfrom C10-C12 is associated with weak basic Pkavalues ranging from 7.2-7.8Pka3-- C4 atom and its substituents exhibitsPka3 ranging from 9.1 to 9.7 which representsstrong alkaline nature.Because of the amphoteric nature tetracyclinesforms water soluble salts with strong acids suchas Hcl and strong bases such NaOH,KoH.
●One of the important property of tetracyclines is their ability to undergoepimerisation at C4 position.●Under acidic condition, tetracycline decline to the elimination reaction of giving offH2O from the C-6 hydroxyl and C-5a hydrogen to generate the inactive 4-epitetracyclines.
Most of the natural tetracyclines have tertiary benzylic hydroxyl group at c-6.Aromatization of ring C under acidic condition occurring as a result ofdehydration reaction, which is accelerated by elevated temperatures. Theelements of H2O derive from the 6-OH and 5a-H atom.65a-H2o-H2o(acid)ABCD(Napthalene derivative)
●Putting the tetracyclines in a basic solution leads tocleavage of ring C from ring B, which leads to theformation of inactive isotetracycline.IsotetracyclineOH--H20
●Chelation is an important feature of the chemical and clinical properties of thetetracyclines.●Tetracyclines are able to form complexes with divalent and trivalent metal ionssuch as Ca2+,Fe2+,Mg2+,Al3+,Fe3+
Tetracyclines inhibit protein synthesis by binding to the bacterial ribosome involved in thetranslation(protein synthesis) process and making them bacteriostatic.The bacterial ribosome is a 70s particle made up of 30s subunit and 50s subunit.The 30s subunit binds mRNA and initiates the protein synthesis.The 50s subunit combines with the 30s subunit-mRNA complex to form a ribisomethen binds aminoacyl tRNA and catalyses the building of the protein chain..There are two main binding sites for the tRNA molecule.The peptidyl(p-site) binds the tRNA bearing the peptide chainThe acceptor aminoacyl site (A-site) Tetracyclines reversibly bind to the 30S subunit at the A-site to prevent attachment of theamino acyl tRNA, terminating the translation process.. .
Freeze initiationBlockpeptidebondformationMisreading of mRNAp-Site(Peptidyl site)on which thet-RNA holds theElongated peptide chain.(A-site)Amino acetylt-RNA bindingsite.(attachment ofIncomming aminoAcid by t-RNA.(Aminoglycosidesblocks translocationhere)ChloramphenicalBlocks transpeptidationTetracyclines reversiblybind to the 30S subunitat the A-site to preventattachment of theamino acyl tRNA,terminating thetranslation process.
What are spectrum of activity ofTetracyclines?Tetracyclines are effective against G+ and G① They are weaker than penicilins andcephalosporins against G+ organisms.② They are weaker than aminoglycosidesand chloramphenicol against Gram(+,-)organisms.
Spectrum of activity:③ They have the favourable effects on* Rickettsiae,* Mycoplasma,* Chlamydiae* Spirochete.④ They are effective against someprotozoa.
Clinical Uses① First choice for rickettsial infections(typhus), chlamydial infections, andMycoplasma pneumonia.② They are effective for many spirochetalinfections, including relapsing fever (firstchoice), leptospirosis, Lyme diseases, andsyphilis.
③ They are also effective for treatment ofvarious G+ and G- bacterial infections.Brucellosis, cholera, and tularemia can betreated with tetracyclines as the firstchoice.④ Other uses: intestinal amebiasis, acne andActinomycosis ect...
Adverse EffectsTetracyclines can produce a varietyof adverse effects ranging fromminor inconvenience to life-threatening.
Hepatic ToxicityMicroscopic study of the liver revealsfine vacuoles, cytoplasmic changes andan increase in fat. Pregnant women areparticularly sensitive to Tetracyclines -induced hepatic damage. Jaundice (increased UREA) azotemia, acidosis,shock. (in pregnant women experiencingpyelonephritis can be fatal)
Renal ToxicityTetracyclines may aggregate uremia inpatients with renal disease by I proteinsynthesis - increased azotemia.Fanconi Syndrome -observed in patients aftertaking outdated and degraded Tetracycline. -clinical picture -nausea, vomiting, polyuria,polydipsia, acidosis, proteinuria, glycosuria
Effects on TEETHChildren receiving long-or shortterm therapy with Tetracyclines maydevelop brown discoloration of theteeth. The drug deposits in the teethand bones probably due to itschelating property and the formationof a Tetracyclines -calciumorthophosphate complex. Thisdiscoloration is permanent. Avoidgiving to pregnant women andchildren under the age of 8.
Other effectsHyersensitivity Rxn -Rash, hives withitching, itching anaphylactic rxn ( decreasein BP, increase in HR, release of histamine,etc.)Photoxicity -1 darkening of skin &sunburn when patient exposed to sunlight
Effects on Microbial AgentsThe Tetracyclines possess a wide range ofantimicrobial activity against gram-positiveand gram-negative bacteria. These drugs areprimarily bacteriostatic. Only multiplyingmicroorganisms are affected. Minocycline isusually the most active followed by doxycyclinethen Tetracyclines and oxytetracycline (leastactive). Strains inhibited by 4 ug/ml or less attetracyclines are considered sensitive.
Finish the prescription.Take on empty stomach.Take with plenty of water.Shake wellAvoid exposure to sun.Do not take with milk, antacids, or iron
* Tetracycline passes into breast milk and may affect boneand tooth development in a nursing baby.* Do not give tetracycline to a child younger than 8 years old.* Avoid exposure to sunlight or artificial UV rays.* Do not take iron supplements, multivitamins,calcium supplements, antacids.* Throw away any unused tetracycline when it expires orwhen it is no longer needed.* Do not use this medication if you are pregnant..
Do not use this medication if you are pregnant..Tetracycline passes into breast milk and may affect bone andtooth development in a nursing baby.Do not give tetracycline to a child younger than 8 years old.Avoid exposure to sunlight or artificial UV rays.Do not take iron supplements, multivitamins, calciumsupplements, antacids.Throw away any unused tetracycline when it expires orwhen it is no longer needed.
•Medicinal and Pharmaceutical chemistry by Daniellednicer• Hari Kishan Singh and V.K.Kapoor•Principles of Organic medicinal chemistry by RamaraoNadendla.•Wilson and Gisvolds text book of Organic and medicinalchemistry.
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