an assessment of the influence of geometric isomerism on the effects of drugs

The structures of geometric isomers are distinguished by the prefixes Z or E preceding the chemical names, the former indicating that a selected pair of substituents are on the same side

MINISTRY OF HEALTH

HANOI UNIVERSITY OF PHARMACY

AN ASSESSMENT OF THE

INFLUENCE OF GEOMETRIC ISOMERISM ON THE EFFECTS OF

DRUGS

By: Team 1 – group 3 – A0K77

HA NOI – 2023

MINISTRY OF HEALTH

HANOI UNIVERSITY OF PHARMACY

AN ASSESSMENT OF THE

INFLUENCE OF GEOMETRIC ISOMERISM ON THE EFFECTS OF

DRUGS

TEAM – GROUP 3 – A0K77 1

Students’ ID Full name Tasks

1 2201077 Trần ị Th Quỳnh Anh Introduction - Thiothixene – Conclusion

– Slide

2 2201452 Lê Thùy Linh Tranexamic Cis/Transplantin acid – Lindane –

3 2201578 Đỗ Phương Ngân Diethylstilbestrol – Thioxanthene – Tranylcypromine

4 2201812 Lê Thu Trang Overview hydroxyamitriptyline - Zimelidine – 10

-5 2201875 Đinh Ngọc Vân Leader - Overview – Cinnamic acid – Doxepin

HA NOI – 2023

TABLE OF CONTENTS

INTRODUCTION 3

I OVERVIEW 4

II THE INFLUENCE OF GEOMETRIC ISOMERISM ON THE EFFECTS OF DRUGS 5

1 Cinnamic Acid 5

2 Doxepin 6

3 Zimelidine 7

4 10-Hydroxyamitriptyline 8

5 Thiothixene 8

6 Diethylstilbestrol 9

7 Clopenthixol 11

8 Tranylcypromine 12

9 A fibrinolysis inhibitor tranexamic acid 12

10 Lindane 14

11 Inorganic coordination compounds: Cisplatin and Transplatin 15

III CONCLUSION 17

IV REFERENCES 18

3

INTRODUCTION

It is possible to organize the atoms in a molecule in variety of ways, as can be seen if we look at the structural formula of butane or other higher hydrocarbons in the alkane or alkyl group It means that it is possible for a single molecular formula to have two or more quite different structural arrangements, a phenomenon known as isomerism

In general, isomers with the same molecular formula and corresponding to the same homologous series tend to have similar chemical properties (since they share the same functional group) but significantly different physical properties

as a consequence of their structural differences The study of isomers is important because even a small change in the structure of molecules can have

a major effect on their physical and chemical properties, especially in the pharmaceutical industry

The following essay takes a look at the effects of geometric isomers on how drugs work and certain instances of medications impacted by geometric isomerism

I OVERVIEW

Stereoisomers are compounds that are identical in atomic constitution and bonding but differ in the three-dimensional arrangement of the atoms This characteristic is arguably one of the most important factors to be considered when designing drugs and assessing their safety [1]

A diastereomer is one of two stereoisomers that are not mirror images of one another and are nonsuperimposable Geometric isomerism was first defined

by Wislicenus in 1887 as isomerism occurring in compounds where rotation

is restricted by double bonds or ring system [2] Geometric isomers do not rotate the plane of polarized light (unless they also contain a chiral center), and hence are not optically active

The structures of geometric isomers are distinguished by the prefixes Z or E preceding the chemical names, the former indicating that a selected pair of substituents are on the same side of the reference plane (cis to each other), andthe latter indicating that they are on opposite sides of the plane (trans to each other) [3] Cis-trans isomers are said to be diastereomers They have different physicochemical properties and pharmacological activity They generally do not fit to the same receptor equally well and if these functional groups are pharmacophores, the isomers will differ in biologic activity [2] al

5

II THE INFLUENCE OF GEOMETRIC ISOMERISM

ON THE EFFECTS OF DRUGS

1 Cinnamic Acid

Mycobacterium tuberculosis is the causative agent of the infectious illness tuberculosis (TB) Multiple-drug resistant tuberculosis (MDR-TB) is a condition that persists despite long-term therapy with a combination of medicines due to adverse side effects and poor patient compliance Therefore,

it is urgent to develop a new, efficient drug or synergist to lower the prevalence

of MDR-TB right now

Cinnamic acid (CA) is a phenolic molecule that occurs naturally and is found

in dietary plant-based foods, herbs, and medications According to reports, CA contains a wide range of biological properties including anti-oxidation, anti-inflammation, anti-cancer, and anti-malaria There are both trans- and cis-isoforms of CA in plants, but due to its great stability, trans- cinnamic acid (t-CA) predominates in the natural world Trans-cinnamic acid (t-CA) can be converted into c -cinnamic acid (c-CA) in the presence of sunshine The isliterature on the biological roles of c-CA is still scarce because it is not widely available Prior to now, scientists had created a workable process for converting c-CA from t-CA and isolating c-CA With the help of the techniques, enough c-CA was produced to test its antituberculosis effectiveness The antituberculosis activity of c-CA was approximately 120-fold of t-CA The development of c-CA as an anti-mycobacterial or synergistic agent could help fight tuberculosis Numerous studies have demonstrated that c-CA differs from t-CA in terms of its physical and chemical properties as well

as exerting higher physiological activity in many areas However, due to its

unavailability, there is still little information in the literature about the biological functions of c-CA both in vitro and in vivo [4]

2 Doxepin

Doxepin, 11-(3-dimethylaminopropylidene)-6H di- -benz[b,e]oxepin, is

related to imipramine and amitriptyline in structure [5]

The geometric isomers in commercial doxepin have a Z:E ratio of 15:85 Compared to the corresponding E-isomers, Z-doxepin and its metabolite Z-N-desmethyldoxepin are both potent antidepressants It has been proposed that the total plasma concentration of Z- & E-doxepin and Z- & E-N-desmethyldoxepin may exhibit a better association with antidepressant effects than the parent medication alone (Faulkner et al 1983) The N-desmethyl metabolite is also known to be active [6]

Only doxepin and desmethyldoxepin, which share the same Z- -E ratio as todoxepin itself, are found in rat brain, even though numerous metabolites of doxepin have been seen in various species Other than desmethyldoxepin, there are presumably no other active metabolites [7]

7

3 Zimelidine

This drug was comparable in antidepressant efficacy to the first-generation tricyclic antidepressants, and it was believed to possess less severe side effects [8] However, this has proved not to be the case, and zimelidine (ZLD) has been withdrawn by its manufacturer because of a relatively high incidence of potentially severe neurological disorders, including Guillain- Barre syndrome [3]

was marketed as the pure Z-isomer Its antidepressant activity has been Itcompared with that of the E-isomer which was prepared fo comparison r purposes The E form was the more potent NE uptake inhibitor, whereas the Z-isomer was much more potent as a 5-HT uptake inhibitor Although the Z form possessed antidepressant activity, it did not prevent reserpine-induced hypothermia, while the E-isomer did [8] This suggests that the reserpine antagonism test's applicability in identifying antidepressant efficacy in new drugs is under doubt [3]

Norzimelidine (NZLD) is a major metabolite of ZLD in man and other species The Z-isomer of NZLD is a more potent inhibitor of 5-HT uptake than (Z)-ZLD [8]

In rats, however, the predominant isomer is (E)-OH-AMT Its formation is stereoselective; the glucuronide of the (-)-enantiomer is excreted in much greater quantity than that of the (+)-enantiomer [9] Since these metabolites could contribute to the antidepressant action of AMT, their pharmacological effects are of interest Bertilsson et al [10] determined that both isomers are similar one another in their abilities to inhibit NE and 5-HT uptake Other tostudies on the effects of hydroxylated metabolites of tricyclic antidepressants

on uptake biogenic amines have been reported and reviewed [11] of

5 Thiothixene

Thiothixene, which has the IUPAC name of N,N-dimethyl-O- piperaziny1)pro-pylidene]-thioxanthene-2-sulfonamide, and trades under the name Navane, is a low-dose antipsychotic drug that is categorized in the group

[3-(4-methyl-1-of thioxanthene drugs

9

Thiothixene is used in the therapy of several psychoses, such as schizophrenia, schizoaffective disorder, delirium, mania, bipolar disorder, dementia with agitation and in behavioral disturbances

Geometric research demonstrates that the distorted hexagonal structure of the phenyl rings of this molecule causes the C-C bonds where substitution groups are linked to be longer than the other phenyl ring bond lengths The calculated energy levels and the relative energy of the trans and cis structures of the molecule show that the cis structure is more stable than the trans structure, with a small energy difference The HOMO energy levels of the trans structure

of thiothixene are slightly lower than the HOMO energy levels of the cis structure, while the LUMO energy levels of the trans structure are higher than those of the cis structure Therefore, the HLG of the trans structure of thiothixene is larger than the HLG of the cis structure TDDFT calculations show that the cis structure of thiothixene has the better absorption properties, while the superior properties of the cis structure of thiothixene can be attributed to the better properties of cis-thiothixene as an active medicine The chemical hardness of the cis structure of thiothixene is lower than that of the trans structure, and the electronegativity, chemical softness, and electrophilicity index of the cis structure of thiothixene are greater than those

of the trans structure This means that the reactivity and charge transfer of the cis isomer of thiothixene are higher than those of the trans isomer

6 Diethylstilbestrol

Diethylstilbestrol (DES) is a synthetic form of the female hormone estrogen Between 1940 and 1971, it was prescribed to expectant mothers to help avoid

miscarriage, early labor, and related pregnancy problems Even though studies conducted in the 1950s revealed that DES was ineffective at preventing these issues, it was still frequently used to treat menopausal symptoms in women, stop lactation, and stop pregnancy

The estrogenic response of isolated disodium salt of cis-DES was determined

to be approximately 45% of the activity observed for trans-DES using a mouse uterine weight assay The trans-isomer's chemical similarity to estradiol is believed to make it significantly more physiologically active, therefore it appears that the cis-DES test solution's observed considerable activity is a result of the trans-isomer being isomerized in vivo These results may have significance in the use of DES as a ruminant growth promoter since estrogenic response appears not to be restricted solely to the amount of trans isomer content The importance of the trans configuration regarding biological activity is convincingly demonstrated by Walton and Brownlee who showed the trans dipropionate DES derivative to be 600 times more active than the corresponding cis derivative

11

7 Clopenthixol

Thioxanthene is closely related to one of the other groups of antipsychotics (phenothiazines, which also include a triple ring) and contains a core triple ring structure The carbon atom in position 10 of thioxanthenes is swapped out for a nitrogen atom in phenothiazines, which is the primary structural difference between the two classes This C10 shares a double bond with the side chain in thioxanthenes

Clopenthixol exists as 2 stereoisomers, cis(Z)-clopenthixol, which has a stronger antipsychotic activity than the mixture of isomers, and trans (E)-c1openthixol which may be considered inactive The optimum dose of clopenthixol depends on the symptomatology of the patient: schizophrenic patients commonly receive daily doses of 50-200mg but doses as high as 800-900mg have been given; in mania, doses of 200mg may be given; while neurotic and geriatric patients receive I0-25mg daily In a 4-week double-blind trial the clinical effects of cis(Z)-c1openthixol (20mg) were compared with clopenthixol (40mg) during the initial treatment of 20 patients with acute psychosis or exacerbation of chronic psychosis All patients improved and after 4 weeks the average BPRS (Brief Psychiatric Rating Scale) scores were reduced by 63 % for cis(Z)clopenthixol and 61 % for clopenthixol The antipsychotic effects of the 2 drugs were found to be equal so that on a mg/

mg basis cis(Z)-clopenthixol was twice as active as openthixol The side cleffects were found to be mostly extrapyramidal symptoms and drowsiness and were the same in each group

Geometrical structure, electronic and optical properties, electronic absorption spectra, thermodynamic properties, natural charge distribution, MEP analysis, and charge transfer analysis of trans and cis structures of chlorprothixene drug have been investigated with DFT and TDDFT methods The results of the computations show that the calculated quantum quantities of the cis isomer of chlorprothixene are in agreement with the activity of -chlorprothixene as a drug Cis structure of chlorprothixene has slightly better absorption properties than the trans structure on the basis of TDDFT calculations The NLOquantities of the cis structure are higher than the trans structure, and the chemical hardness of the cis isomer, is smaller than the trans isomer which specifies that the reactivity and charge transfer of the cis structure of chlorprothixene is higher than the trans structure

8 Tranylcypromine

Tranylcypromine, which has the IUPAC name of phenylcyclopropanamine, was first synthesized by Burger and Yost It has been extensively studied in terms of stereochemistry for several reasons For instance, the rigidity of the three-membered ring has made it a useful model for considering the dihedral angle of the aromatic ring with respect to the amino group Stereochemistry has also been of interest in comparisons of the cis and trans geometric isomers as well as in comparisons of the R and S enantiomers of 1 Differences in pharmacological effects and potencies between these isomers have been of significance in studies of many arylethylamines and analogs, such as amphetamines and neurotransmitters, as well as in considerations of the structure of active site receptors for these substances

trans-2-9 A fibrinolysis inhibitor tranexamic acid

Tranexamic acid (4-aminomethylcyclohexanecarboxylic acid - AMCHA) is a commonly used substance to treat fibrinolysis and to increase the coagulation

of blood AMCHA works by inhibiting the transformation of plasminogen into plasmin the enzyme breaking down the fibrinogen, which stabilizes in blood